U.S. patent application number 11/451660 was filed with the patent office on 2007-06-07 for modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity, and use thereof.
Invention is credited to Jingwu Duan, Bin Jiang, Zhonghui Lu, David S. Weinstein.
Application Number | 20070129400 11/451660 |
Document ID | / |
Family ID | 37401459 |
Filed Date | 2007-06-07 |
United States Patent
Application |
20070129400 |
Kind Code |
A1 |
Duan; Jingwu ; et
al. |
June 7, 2007 |
Modulators of glucocorticoid receptor, AP-1, and/or NF-kB activity,
and use thereof
Abstract
Non-steroidal compounds are provided which are useful in
treating diseases associated with modulation of the glucocorticoid
receptor, AP-1, and/or NF-.kappa.B activity including obesity,
diabetes, inflammatory and immune diseases, and have the structure
of formula (I) ##STR1## or an enantiomer, a diastereomer, a
pharmaceutically acceptable salt, or hydrate thereof, where J is
selected from NR.sub.1 or C(R.sub.4)(R.sub.4a); K is selected from
NR.sub.2 or C(R.sub.5)(R.sub.5a); L is selected from NR.sub.3 or
C(R.sub.6)(R.sub.6a); and A, X, Y, R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.4a, R.sub.5, R.sub.5a, R.sub.6, R.sub.6a, R.sub.8,
R.sub.10, R.sub.11, and n are defined herein. Also provided are
pharmaceutical compositions and methods of treating obesity,
diabetes and inflammatory or immune associated diseases comprising
said compounds.
Inventors: |
Duan; Jingwu; (Yardley,
PA) ; Lu; Zhonghui; (King of Prussia, PA) ;
Weinstein; David S.; (East Windsor, NJ) ; Jiang;
Bin; (Norristown, PA) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
37401459 |
Appl. No.: |
11/451660 |
Filed: |
June 13, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60690355 |
Jun 14, 2005 |
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60782636 |
Mar 15, 2006 |
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Current U.S.
Class: |
514/314 ;
514/338; 514/365; 514/367; 514/406; 546/176; 546/275.7; 548/159;
548/181; 548/361.1 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 27/16 20180101; A61P 21/04 20180101; A61P 35/02 20180101; A61P
3/10 20180101; A61P 25/18 20180101; A61P 27/14 20180101; A61P 9/08
20180101; A61P 19/10 20180101; A61P 37/04 20180101; A61P 31/18
20180101; A61P 29/00 20180101; A61P 7/04 20180101; A61P 31/10
20180101; C07D 401/06 20130101; C07D 405/06 20130101; C07D 417/06
20130101; A61P 9/12 20180101; A61P 17/04 20180101; A61P 43/00
20180101; A61P 11/00 20180101; A61P 17/08 20180101; C07D 409/06
20130101; A61P 17/14 20180101; A61P 21/00 20180101; A61P 5/00
20180101; A61P 5/40 20180101; A61P 37/02 20180101; A61P 37/06
20180101; A61P 17/00 20180101; A61P 5/14 20180101; C07D 231/56
20130101; A61P 7/00 20180101; A61P 17/02 20180101; A61P 3/04
20180101; A61P 3/14 20180101; A61P 25/24 20180101; A61P 35/00
20180101; C07D 405/04 20130101; A61P 1/16 20180101; A61P 37/08
20180101; A61P 1/04 20180101; A61P 17/06 20180101; C07D 417/12
20130101; A61P 11/06 20180101; A61P 27/02 20180101; C07D 401/04
20130101; A61P 9/00 20180101; A61P 9/10 20180101; A61P 19/06
20180101; A61P 31/06 20180101; A61P 27/06 20180101; A61P 7/06
20180101; C07D 403/04 20130101; A61P 1/18 20180101; A61P 25/00
20180101; A61P 13/12 20180101 |
Class at
Publication: |
514/314 ;
514/406; 514/338; 514/365; 514/367; 546/176; 546/275.7; 548/181;
548/159; 548/361.1 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 31/4439 20060101 A61K031/4439; A61K 31/428
20060101 A61K031/428; A61K 31/427 20060101 A61K031/427; A61K 31/416
20060101 A61K031/416; C07D 417/02 20060101 C07D417/02; C07D 403/02
20060101 C07D403/02; C07D 405/02 20060101 C07D405/02; C07D 409/02
20060101 C07D409/02 |
Claims
1. A compound represented by Formula I ##STR23## or a
pharmaceutically acceptable salt thereof, wherein: is a single or
double bond; A is a partially saturated ring; n is 0, 1, or 2; is
NR.sub.1 or C(R.sub.4)(R.sub.4a); K is NR.sub.2 or
C(R.sub.5)(R.sub.5a); L is NR.sub.3 or C(R.sub.6)(R.sub.6a); X is a
bond, alkylene, alkenylene, alkynylene, --C(O), --N(R.sub.14)--,
--N(R.sub.14)alkylene-, --Oalkylene-, --N(R.sub.14)--C(O)--,
--N(R.sub.14)--C(O)O--, --NR.sub.15C(O)NR.sub.16, --S(O).sub.t--
##STR24## Y is selected from hydrogen, halogen, nitro, cyano;
OR.sub.12, NR.sub.12R.sub.13, C(.dbd.O)R.sub.12, CO.sub.2R.sub.12,
C(.dbd.O)NR.sub.12R.sub.13, O--C(.dbd.O)NR.sub.12R.sub.13,
--O--C(.dbd.O)R.sub.12, NR.sub.12C(.dbd.O)R.sub.13,
NR.sub.12C(O)OR.sub.13, NR.sub.12C(O)N(R.sub.13).sub.2,
NR.sub.12C(S)OR.sub.13, S(O).sub.pR.sub.20,
NR.sub.12S(O).sub.pN(R.sub.13).sub.2, NR.sub.12S(O).sub.pR.sub.20,
and S(O).sub.pNR.sub.12R.sub.13; or Y is taken together with
R.sub.8 to form an oxo, a substituted alkenyl, or an unsubstituted
alkenyl; R.sub.1 is selected from (i) alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
OR.sub.14, NR.sub.14S(O).sub.pR.sub.21, cycloalkyl, heterocyclo,
aryl, and heteroaryl; and/or (ii) R.sub.1 is taken together with
R.sub.2 or R.sub.2 is taken together with R.sub.3 to form a double
bond; R.sub.2, and R.sub.3 are independently selected from (i)
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, OR.sub.14,
NR.sub.14S(O).sub.pR.sub.21, cycloalkyl, heterocyclo, aryl, and
heteroaryl; and/or (ii) R.sub.1 is taken together with R.sub.2 or
R.sub.2 is taken together with R.sub.3 to form a double bond;
R.sub.4, R.sub.4a, R.sub.5, R.sub.5a, R.sub.6, and R.sub.6a are
independently selected from (i) hydrogen, halogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, azide, cyano, OR.sub.15,
NR.sub.15R.sub.16, C(.dbd.O)R).sub.5, CO.sub.2R.sub.15,
C(.dbd.O)NR.sub.15R.sub.16, O--C(.dbd.O)NR.sub.12R.sub.13,
--O--C(.dbd.O)R.sub.15, NR.sub.15C(.dbd.O)R.sub.16,
NR.sub.15C(O)OR.sub.16, NR.sub.15C(S)OR.sub.16, S(O).sub.qR.sub.22,
NR.sub.15S(O).sub.qR.sub.22, S(O).sub.qNR.sub.15R.sub.16,
cycloalkyl, heterocyclo, aryl, and heteroaryl; and/or (ii) R.sub.4
may be taken together with R.sub.4a, and/or R.sub.5 may be taken
together with R.sub.5a, and/or R.sub.6 may be taken together with
R.sub.6a to form an oxo, alkenyl, or substituted alkenyl group;
and/or (iii) each one of R.sub.4, R.sub.4a, R.sub.5, R.sub.5a,
R.sub.6, and R.sub.6a is taken together with any one of R.sub.4,
R.sub.4a, R.sub.5, R.sub.5a, R.sub.6, and R.sub.6a located on an
adjacent carbon atom to form a double bond or a fused ring; or when
J is NR.sub.1, and/or K is NR.sub.2, and/or L is NR.sub.3, each one
of R.sub.1, R.sub.2, and/or R.sub.3 is taken together with one of
R.sub.4, R.sub.4a, R.sub.5, R.sub.5a, R.sub.6, and R.sub.6a which
is located on an adjacent carbon atom to form a double bond;
R.sub.8 and R.sub.10 are independently selected from (i) hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, OR.sub.17, S(O).sub.rR.sub.23,
NR.sub.17S(O).sub.rR.sub.23, cycloalkyl, heterocyclo, aryl, and
heteroaryl; or (ii) R.sub.8 is taken together with R.sub.10 to form
a cycloalkyl, heterocyclo, aryl, and heteroaryl ring; and/or (iii)
R.sub.8 is taken together with Y to form an oxo, alkenyl, or a
substituted alkenyl group; R.sub.11 at each occurrence is
independently selected from (i) alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, halogen, nitro,
azide, cyano, OR.sub.19, cycloalkyl,-heterocyclo, aryl, and
heteroaryl; and/or (ii) two R.sub.1 groups located on the same
carbon atom are taken together to form an oxo, alkenyl, or a
substituted alkenyl group; R.sub.12, R.sub.13, R.sub.14, R.sub.15,
R.sub.16, R.sub.17, R.sub.18, and R.sub.19 at each occurrence are
independently selected from (i) hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R.sub.12 is
taken together with R.sub.13 and/or R.sub.15 is taken together with
R.sub.16 to form a heteroaryl or heterocyclo ring; R.sub.20,
R.sub.21, R.sub.22, and R.sub.23 are independently selected from
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
and p, q, r and t are independently selected from 0, 1 and 2;
provided that: a) the compound has a CAS registry number other than
116373-85-4 and 344573-23-5; and b) where R.sub.1 is substituted or
unsubstituted phenyl, R.sub.6 and R.sub.6a are other than
phenyl.
2. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein: J is NR.sub.1; K is NR.sub.2; L
is C(R.sub.6)(R.sub.6a); and R.sub.2 and R.sub.6a are joined
together to form a double bond.
3. The compound according to claim 2, or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is cycloalkyl, aryl,
heterocyclo, or heteroaryl, wherein said cycloalkyl, aryl,
heterocyclo, or heteroaryl is substituted with from one up to the
maximum number of substitutable positions with a substituent
independently selected from hydrogen, halogen, nitro, cyano,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl, substituted
C.sub.2-6alkynyl, OR.sub.a, C(.dbd.O)NR.sub.aR.sub.b,
C(.dbd.O)R.sub.a, CO.sub.2R.sub.a, --O--C(.dbd.O)NR.sub.aR.sub.b,
C(.dbd.O)NR.sub.aR.sub.b, --O--C(.dbd.O)R.sub.a,
NR.sub.aC(.dbd.O)R.sub.b, NR.sub.aC(O)OR.sub.b,
NR.sub.aC(S)OR.sub.b, S(O),R.sub.c, NR.sub.aS(O).sub.sR.sub.c,
S(O).sub.pNR.sub.aR.sub.b, cycloalkyl, heterocyclo, aryl, and
heteroaryl; R.sub.a and R.sub.b at each occurrence are
independently selected from (i) hydrogen, alkyl,, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R.sub.a is
taken together with R.sub.b to form a heteroaryl or heterocyclo
ring; R.sub.c is selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; and s is 1 or 2.
4. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is aryl or heteroaryl,
each of which is substituted with 0-3 groups selected from
hydrogen, halogen, nitro, cyano, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl, OR.sub.a, NR.sub.aR.sub.b,
C(.dbd.O)NR.sub.aR.sub.b, S(O).sub.sR.sub.c,
NR.sub.aS(O).sub.sR.sub.c, S(O).sub.pNR.sub.aR.sub.b, and
C.sub.3-7cycloalkyl.
5. The compound according to claim 2, or a pharmaceutically
acceptable salt thereof, wherein: X is a bond, alkylene,
--N(R.sub.14)--, --N(R.sub.14)alkylene-, --N(R.sub.14)C(O)--,
--Oalkylene-, --NR.sub.15C(O)NR.sub.16--, --S(O).sub.t--,
--OC(O)NH--, or --OC(O)O--; Y is (i) hydrogen, OR.sub.12,
NR.sub.12R.sub.13, or O--C(--O)NR.sub.12R.sub.13; or (ii) Y
together with R.sub.8 combines to form oxo or alkenyl; R.sub.8 is
(i) hydrogen, alkyl, substituted alkyl; or (ii) R.sub.8 together
with Y forms oxo or alkenyl; or (iii) R.sub.8 together with
R.sub.10 combines to form heterocyclo; R.sub.10 is (i) hydrogen,
hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, or substituted alkynyl; or (ii) cycloalkyl, aryl,
heterocyclo, or heteroaryl; wherein said cycloalkyl, aryl,
heterocyclo, or heteroaryl is optionally substituted with from one
up to the maximum number of substitutable positions with a
substituent independently selected from the group consisting of
halogen, nitro, cyano, C.sub.1-6alkyl, oxo, N-oxide, substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl,
C.sub.2-6alkynyl, substituted C.sub.2-6alkynyl, OR.sub.d,
NR.sub.dR.sub.e, C(.dbd.O)R.sub.d, CO.sub.2R.sub.d,
--O--C(.dbd.O)NR.sub.dR.sub.e, C(.dbd.O)NR.sub.dR.sub.e,
--O--C(.dbd.O)R.sub.d, NR.sub.dC(.dbd.O)R.sub.d,
NR.sub.dC(O)OR.sub.e, NR.sub.dC(S)OR.sub.e, S(O).sub.vR.sub.f,
NR.sub.dS(O).sub.vR.sub.f, S(O).sub.vNR.sub.dR.sub.e, cycloalkyl,
heterocyclo, aryl, and heteroaryl; R.sub.d and R.sub.e at each
occurrence are independently selected from (i) hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
and/or (ii) R.sub.d is taken together with R.sub.e to form a
heteroaryl or heterocyclo ring; R.sub.f is selected from hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
and v is 1 or 2.
6. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein: X is a bond, alkylene,
alkenylene, alkynylene, --C(O), --N(R.sub.14)--,
--N(R.sub.14)--C(O)--, or ##STR25## Y is selected from hydrogen,
halogen, nitro, cyano; OR.sub.12, NR.sub.12R.sub.13,
C(--O)R.sub.12, CO.sub.2R.sub.12, C(.dbd.O)NR.sub.12R.sub.13,
O--C(.dbd.O)NR.sub.12R.sub.13, --O--C(.dbd.O)R.sub.12,
NR.sub.12C(.dbd.O)R.sub.13, NR.sub.12C(O)OR.sub.13,
NR.sub.12C(S)OR.sub.13, S(O).sub.pR.sub.20,
NR.sub.12S(O).sub.pN(R.sub.13).sub.2, NR.sub.12S(O).sub.pR.sub.20,
and S(O).sub.pNR.sub.12R.sub.13,; R.sub.8 and R.sub.10 are
independently selected from (i) hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
OR.sub.17, S(O).sub.rR.sub.23, NR.sub.17S(O).sub.rR.sub.23,
cycloalkyl, heterocyclo, aryl, and heteroaryl; or (ii) R.sub.8 may
be taken together with R.sub.10 to form a ring; R.sub.11 at each
occurrence is independently selected from alkyl, substituted alkyl,
alkenyl, substituted alkenyl, halogen, cyano, nitro, OR.sub.19,
cycloalkyl, heterocyclo, aryl, and heteroaryl; and p, q, and r are
independently selected from 1 and 2.
7. A compound according to claim 1, having Formula II ##STR26## or
a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, or a pharmaceutically
acceptable salt thereof, wherein: X is a (i) a bond, alkylene,
--N(R.sub.14)--, --N(R.sub.14)alkylene-, --N(R.sub.14)C(O)--,
--Oalkylene-, --NR.sub.15C(O)NR.sub.16--, --S(O).sub.t--,
--OC(O)N(R.sub.14)--, or --OC(O)O--; C(.dbd.O)N(R.sub.14)--, Y is
(i) hydrogen, OR.sub.12, NR.sub.12R.sub.13, or
O--C(.dbd.O)NR.sub.12R.sub.13; or (ii) Y is taken together with
R.sub.8 to form oxo or alkenyl; R.sub.1 is aryl or heteroaryl
substituted with 1-3 groups selected from hydrogen, halogen, nitro,
cyano, C.sub.1-6alkyl, substituted C.sub.1-6alkyl, OR.sub.a,
NR.sub.aR.sub.b, C(.dbd.O)NR.sub.aR.sub.b, S(O).sub.sR.sub.e,
NR.sub.aS(O).sub.sR.sub.c, S(O).sub.pNR.sub.aR.sub.b, and
C.sub.3-5cycloalkyl; R.sub.8 is (i) hydrogen, C.sub.1-6alkyl, or
substituted C.sub.1-6alkyl; or (ii) R.sub.8 is taken together with
Y to form oxo or alkenyl; or (iii) R.sub.8 is combined with
R.sub.10 to form heterocyclo; R.sub.10 is (i) hydrogen, hydroxy,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or
substituted alkynyl; or (ii) cycloalkyl, aryl, heterocyclo, or
heteroaryl; said cycloalkyl, aryl, heterocyclo, or heteroaryl
optionally substituted with from one up to the maximum number of
substitutable positions with substituents independently selected
from hydrogen, halogen, nitro, cyano C.sub.1-6alkyl, oxo, N-oxide,
substituted C.sub.1-6alkyl, C.sub.2-6alkenyl, substituted
C.sub.2-6alkenyl, C.sub.2-6alkynyl, substituted C.sub.2-6alkynyl,
OR.sub.d, NR.sub.dR.sub.e, C(.dbd.O)R.sub.d, CO.sub.2R.sub.d,
--O--C(.dbd.O)NR.sub.dR.sub.e, C(.dbd.O)NR.sub.dR.sub.e,
--O--C(.dbd.O)R.sub.d, NR.sub.dC(.dbd.O)R.sub.e,
NR.sub.dC(O)OR.sub.e, NR.sub.dC(S)OR.sub.e, S(O).sub.vR.sub.f,
N.sub.dS(O).sub.vR.sub.f, S(O).sub.vNR.sub.dR.sub.e, cycloalkyl,
heterocyclo, aryl, and heteroaryl; each R.sub.11 is (i)
independently selected from hydrogen, halogen, cyano, nitro,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, cycloalkyl, OR.sub.19,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, alkynyl,
substituted alkynyl, and C.sub.3-6cycloalkyl; and/or (ii) two
R.sub.11 groups located on the same carbon atom are taken together
to form an oxo group; R.sub.12 and R.sub.13 are independently
selected from hydrogen, C.sub.1-6alkyl, substituted C.sub.1-6alkyl,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl,
substituted C.sub.2-6alkynyl, C.sub.3-7 cycloalkyl,
C.sub.2-6alkenyl, or acetyl; R.sub.a, R.sub.b, R.sub.d and R.sub.e
at each occurrence are independently selected from (i) hydrogen,
alkyl, , substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) R.sub.a is taken together with R.sub.b and/or R.sub.d is
taken together with R.sub.e to form a heteroaryl or heterocyclo
ring; R.sub.c and R.sub.f at each occurrence are independently
selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl,
heteroaryl, and heterocyclo; and v is 1 or 2.
9. A compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein: n is 0 or 1; X is a (i) a bond;
or (ii) C.sub.1-4alkylene or C.sub.2-4alkenylene, each of which is
substituted with one to three groups selected from hydrogen,
halogen, OH, OCH.sub.3, and OCF.sub.3; Y is OR.sub.12; R.sub.8 is
(i) hydrogen, C.sub.1-6alkyl, or substituted C.sub.1-6alkyl; or
(ii) R.sub.8 is combined with Y to form .dbd.O; R.sub.10 is
selected from the group consisting of: (i) hydroxy, C.sub.1-6alkyl,
substituted C.sub.1-6alkyl, C.sub.2-6alkenyl, substituted
C.sub.2-6alkenyl, C.sub.2-6alkynyl, substituted C.sub.2-6alkynyl,
and C.sub.3-6cycloalkyl; or (ii) phenyl, phenylsulfonyl, napthyl,
quinolinyl, pyrrolyl, pyridyl, thiazolyl, benzothiazolyl, thienyl,,
benzothienyl, furyl, and benzofuryl, each group of which is
optionally further substituted by one up to the maximum number of
substitutable positions with a substituent independently selected
from halogen, CN, NR.sub.dR.sub.e, C.sub.1-6alkyl, OH,
OC.sub.1-6alkyl, OCF.sub.3, CF.sub.3, --O (optionally substituted
phenyl), or --O (optionally substituted benzyl); R.sub.d and
R.sub.e are independently selected (i) from hydrogen,
C.sub.1-6alkyl, and substituted C.sub.1-16alkyl; or (ii) R.sub.d is
taken together with R.sub.e to form a heteroaryl or heterocyclo
ring; each R.sub.11 is independently selected from C.sub.1-6alkyl,
substituted C.sub.1-6alkyl, C.sub.2-6alkenyl, substituted
C.sub.2-6alkenyl, and C.sub.3-6cycloalkyl; and R.sub.12 is hydrogen
or C.sub.1-6alkyl.
10. A compound according to claim 8 having Formula III: ##STR27##
or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is
phenyl substituted with 1-3 groups selected from halogen, nitro,
cyano, methyl, methoxy, ethoxy, nitro, cyano, and CF.sub.3;
R.sub.11b and R.sub.11c are independently selected from hydrogen,
halogen, nitro, cyano, C.sub.1-6alkyl, substituted C.sub.1-6alkyl,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl,
substituted C.sub.2-6alkynyl, and C.sub.3-7cycloalkyl.
11. A compound according to claim 10, or a pharmaceutically
acceptable salt thereof, wherein: X is a bond, alkylene, or
--N(R.sub.14)--; Y is (i) hydrogen or OR.sub.12; or (ii) Y is taken
together with R.sub.8 to form oxo; R.sub.8 is (i) hydrogen,
CF.sub.3, or CH.sub.3; or (ii) R.sub.8 is taken together with Y to
form oxo. R.sub.10 is selected from the group consisting of: (i)
hydrogen, hydroxy, C.sub.1-6alkyl, substituted C.sub.1-6alkyl,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl,
substituted C.sub.2-6alkynyl, and C.sub.3-6cycloalkyl; or (ii)
cyclopentyl, cyclohexyl, phenyl, phenylsulfonyl, napthyl,
quinolinyl, pyrrolyl, pyridyl, thiazolyl, thiadiazolyl,
benzothiazolyl, thienyl,, benzothienyl, furyl,
1,3-dihydroisobenzofuryl, and benzofuryl, each group of which is
optionally further substituted by one up to the maximum number of
substitutable positions with a substituent independently selected
from halogen, CN, NR.sub.dR.sub.e, N-oxide, C.sub.1-6alkyl,
substituted C.sub.1-6alkyl, OH, OC.sub.1-6alkyl, OCF.sub.3,
CF.sub.3, phenyl, pyrrolyl, morpholinyl, --O (optionally
substituted phenyl), or --O (optionally substituted benzyl); or
(iii) R.sub.8 is combined with R.sub.10 to form benozdioxinyl or
dioxolanyl; and R.sub.14 is selected from hydrogen, C.sub.1-6alkyl,
and --C(O)C.sub.1-6alkyl; v is 1 or 2.
12. A compound according to claim 11, or a pharmaceutically
acceptable salt thereof, wherein: X is a bond, methylene, ethylene,
butylene, or --N(R.sub.14)--; R.sub.12 and R.sub.13 are
independently selected from hydrogen, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl, acetyl, C.sub.2-6alkenyl, and
--OC(O)NHC.sub.1-6alkyl; R.sub.14 is selected from hydrogen, ethyl,
and --C(O)Me; R.sub.d and R.sub.e are independently (i) hydrogen,
C.sub.1-6alkyl, or substituted C.sub.1-6alkyl; or (ii) R.sub.d is
taken together with R.sub.e to form a heteroaryl or heterocyclo
ring; R.sub.f is selected from hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl, and heterocyclo; and v is 1 or 2.
13. A compound according to claim 10 having Formula IV: ##STR28##
or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 13, or a pharmaceutically
acceptable salt thereof, wherein: X is a bond; Y is
--OC.sub.1-6alkyl or --OC.sub.2-6alkenyl; R.sub.8 is hydrogen;
R.sub.10 is an optionally substituted phenyl group; R.sub.11b is
hydrogen, acetylenyl, cyano, chloro, or C.sub.1-6alkyl; and n is
1.
15. A compound according to claim 13, or a pharmaceutically
acceptable salt thereof, wherein: X is --NH--; Y is taken together
with R.sub.8 to form oxo; R.sub.10 is an optionally substituted
five-membered heteroaryl group; R.sub.11b is C.sub.1-6alkyl; and n
is 2.
16. A compound according to claim 1 selected from: (i) Example 1
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-p-
henylethanol); Example 2
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-p-
henylethanol); Example 3
(1-(4-fluorophenyl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]ethanol); Example 4
(1-(4-fluorophenyl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]ethanol); Example 5
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-[-
4-(methyloxy)phenyl]ethanol); Example 6
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-[-
4-(methyloxy)phenyl]ethanol); Example 7
(1-(4-fluorophenyl)-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]propan-2-ol); Example 8
(1-(4-fluorophenyl)-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]propan-2-ol); Example 9
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]hex--
5-en-2-ol); Example 10
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]hex--
5-en-2-ol); Example 11
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-1-ylethanol); Example 12
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-1-ylethanol); Example 13
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-2-ylethanol); Example 14
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-2-ylethanol); Example 15
(1-biphenyl-2-yl-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]ethanol); Example 16
(1-biphenyl-2-yl-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]ethanol); Example 17
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
3-thienyl)ethanol); Example 18
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
3-thienyl)ethanol); Example 19
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
2-thienyl)ethanol); Example 20
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
2-thienyl)ethanol); Example 21
(1-(1-benzothien-3-yl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl]ethanol); Example 22
(1-(1-benzothien-3-yl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl]ethanol); Example 23
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]etha-
nol); Example 24
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-p-
henylethanone); Example 25
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-2-p-
henylpropan-2-o);1 Example 26
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-2-p-
henylpropan-2-ol); Example 27
(1,1,1-trifluoro-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]-2-phenylpropan-2-ol); Example 28
(1,1,1-trifluoro-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]-2-phenylpropan-2-ol); Example 29
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-phenylethanol); Example 30
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-phenylethanol); Example 31
(2-[(5S)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-phenylethanol); Example 32
(2-[(5S)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-phenylethanol); Example 33
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-(2-thienyl)ethanol); Example 34
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-(2-thienyl)ethanol); Example 35
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-phenylethyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole); Example 36
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihy-
dro-1H-indazole); Example 37
((5R)-5-(2-(benzyloxy)-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 38
((5R)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-phenyl-2-propoxyethyl)-4,5-dih-
ydro-1H-indazole); Example 39
((5R)-5-(2-(allyloxy)-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 40
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-
-phenylethyl methylcarbamate); Example 41
((5R)-1-(4-fluorophenyl)-5-(2-isopropoxy-2-phenylethyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 42
((5R)-5-(2-cyclobutoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 43
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(naphthalen-1-yl)ethyl)-5,6-dimet-
hyl-4,5-dihydro-1 1H-indazole); Example 44
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(naphthalen-1-yl)ethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 45
((5R)-1-(4-fluorophenyl)-5-(2-(4-fluorophenyl)-2-methoxyethyl)-5,6-dimeth-
yl-4,5-dihydro-1H-indazole); Example 46
((5R)-5-(2-ethoxy-2-(4-fluorophenyl)ethyl)-1-(4-fluorophenyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole); Example 47
((5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-(2-methoxy-2-phenylethyl)-5-meth-
yl-4,5-dihydro-1H-indazole); Example 48
(1-(biphenyl-3-yl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazol-5-yl)ethanol); Example 49
(1-(biphenyl-3-yl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazol-5-yl)ethanol); Example 50
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-m--
tolylethanol); Example 51
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-m--
tolylethanol); Example 52
((5R)-5-(2-ethoxy-2-m-tolylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole); Example 53
(1-(3-fluorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 54
(1-(3-fluorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 55
((5R)-5-(2-ethoxy-2-(3-fluorophenyl)ethyl)-1-(4-fluorophenyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole); Example 56
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxyphenyl)ethanol); Example 57
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxyphenyl)ethanol); Example 58
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(2-methoxyphenyl)ethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 59
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-o--
tolylethanol); Example 60
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-o--
tolylethanol); Example 61
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole); Example 62
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole); Example 63
((5R)-5-(2-ethoxy-2-o-tolylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole); Example 64
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5,6,-
7-tetrahydro-1H-indazole); Example 65
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methoxyphenyl)ethanol); Example 66
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methoxyphenyl)ethanolv Example 67
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methylthiophen-2-yl)ethanol); Example 68
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methylthiophen-2-yl)ethanol); Example 69
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(5-
-methylthiophen-2-yl)ethanol); Example 70
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(5-
-methylthiophen-2-yl)ethanol); Example 71
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(t-
hiazol-2-yl)ethanol); Example 72
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(t-
hiazol-2-yl)ethanol); Example 73
(1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)but-3-
-yn-2-ol); Example 74
(1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)but-3-
-yn-2-ol); Example 75
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-2-yl)ethanol); Example 76
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-2-yl)ethanol); Example 77
((R)-5-(2-ethoxy-2-(pyridin-2-yl)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4-
,5-dihydro-1H-indazole); Example 78
(2-(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-
-hydroxyethyl)pyridine 1-oxide); Example 79
(2-(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-
-hydroxyethyl)pyridine 1-oxide); Example 80
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-3-yl)ethanol); Example 81
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-3-yl)ethanol); Example 82
(1-(2,6-dimethylphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl)ethanol); Example 83
(1-(2,6-dimethylphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl)ethanol); Example 84
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methylnaphthalen-1-yl)ethanol); Example 85
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methylnaphthalen-1-yl)ethanol); Example 86
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxynaphthalen-1-yl)ethanol); Example 87
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxynaphthalen-1-yl)ethanol); Example 88
(1-(2,6-dimethoxyphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazol-5-yl)ethanol); Example 89
(1-(2,6-dimethoxyphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazol-5-yl)ethanol); Example 90
(1-cyclopentyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)ethanol); Example 91
(1-cyclopentyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)ethanol); Example 92
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-(pyrrolidin-1-ylmethyl)phenyl)ethanol); Example 93
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-(pyrrolidin-1-ylmethyl)phenyl)ethanol); Example 94
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-(morpholinomethyl)phenyl)ethanol); Example 95
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-(morpholinomethyl)phenyl)ethanol); Example 96
(1-(2-chlorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 97
(1-(2-chlorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 98
((5R)-5-(2-(2-chlorophenyl)-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole); Example 99
((5R)-5-((1,3-dihydroisobenzofuran-1-yl)methyl)-1-(4-fluorophenyl)-5,6-di-
methyl-4,5-dihydro-1H-indazole); Example 100
((5R)-5-((1,3-dihydroisobenzofuran-1-yl)methyl)-1-(4-fluorophenyl)-5,6-di-
methyl-4,5-dihydro-1H-indazole); Example 101
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(4-
-methylthiazol-2-yl)ethanol); Example 102
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(4-
-methylthiazol-2-yl)ethanol); Example 103
(2-(1-ethoxy-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)ethyl)-4-methylthiazole); Example 104
(2-(1-ethoxy-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)ethyl)-4-methylthiazole); Example 10S
(1-cyclohexyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indaz-
ol-5-yl)ethanol); Example 106
(1-cyclohexyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indaz-
ol-5-yl)ethanol); Example 107
((5R)-5-(2-cyclohexyl-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 108
((5R)-5-(2-cyclohexyl-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 109
((R)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-ph-
enylpentan-2-ol); Example 110
((R)-2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-ph-
enylethanamine); Example 111
((R)-N-(2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-
-phenylethyl)acetamide); Example 112
((R)-N,N-diethyl-2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)-1-phenylethanamine); Example 113
(N-ethyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5--
yl)-1-phenylethanamine); Example 114
(N-ethyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5--
yl)-1-phenylethanamine); Example 115
(2-((5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-5--
yl)-1-phenylethanol); Example 116
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5,6,7--
tetrahydro-1H-indazole); Example 117
(2-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1-phe-
nylethanol); Example 118
(2-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1-phe-
nylethanol); Example 119
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydr-
o-1H-indazole); Example 120
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydr-
o-1H-indazole); Example 121
(2-(1-(4-fluorophenyl)-5-methyl-6-(trifluoromethyl)-4,5-dihydro-1H-indazo-
l-5-yl)-1-phenylethanol); Example 122
(2-(1-(4-fluorophenyl)-5-methyl-6-(trifluoromethyl)-4,5-dihydro-1H-indazo-
l-5-yl)-1-phenylethanol); Example 123
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-6-(trifluoromethy-
l)-4,5-dihydro-1H-indazole); Example 124
(((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-
- 1H-indazol-6-yl)methanol); Example 125
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-5-m-
ethyl-4,5-dihydro-1H-indazole); Example 126
(((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-
-1H-indazol-6-yl)methyl pivalate); Example 127
(5R)-5-(2-ethoxy-2-phenylethyl)-6-ethyl-1-(4-fluorophenyl)-5-methyl-4,5-d-
ihydro-1H-indazole); Example 128
((5R)-6-(difluoromethyl)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5--
methyl-4,5-dihydro-1H-indazole); Example 129
(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-1-phenyletha-
nol); Example 130
(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-1-phenyletha-
nol); Example 131
(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-1-phenyletha-
nol); Example 132
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-in-
dazole); Example 133
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-in-
dazole); Example 134
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-in-
dazole); Example 135
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydr-
o-1H-indazol-6-ol); Example 136
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydr-
o-1H-indazol-6-ol); Example 137
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-6-methoxy-5-methyl-4,-
5-dihydro-1H-indazole); Example 138
(2-(1-(4-fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-5--
yl)-1-phenylethanol); Example 139
((R)-N-(2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)et-
hyl)-1,3,4-thiadiazol-2-amine); Example 140
((R)-5-(2-(benzyloxy)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazole); Example 141
((R)-N-benzyl-2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-
-yl)ethanamine); Example 142
((S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-phenylallyl)-4,5-dihydro-1H-ind-
azole); Example 143
((R,E)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-(naphthalen-1-yl)vinyl)-4,5-d-
ihydro-1H-indazole); Example 144
((R)-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)(ph-
enyl)methanol); Example 145
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-ph-
enylethanol); Example 146
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-phenylpropan-1-ol); Example 147
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-phenylpropan-1-ol); Example 148
((S)-1-(4-fluorophenyl)-5-((R)-1-methoxy-3-phenylpropyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 149
((S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-phen-
ylpropan-1-one); Example 150
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-methyl-3-phenylbutan-1-ol); Example 151
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-methyl-3-phenylbutan-1-ol); Example 152
((S)-1-(4-fluorophenyl)-5-((R)-1-methoxy-3-methyl-3-phenylbutyl)-5,6-dime-
thyl-4,5-dihydro-1H-indazole); Example 153
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-me-
thyl-3-phenylbutan-1-one); Example 154
((S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylthiomethyl)-4,5-dihydro-1H--
indazole); Example 155
((5S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylsulfinylmethyl)-4,5-dihydr-
o-1H-indazole); Example 156
((S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylsulfonylmethyl)-4,5-dihydro-
-1H-indazole); Example 157 ((S)-allyl
1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-ylcarbamate);
Example 158 ((S)-benzyl
1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-ylcarbamate);
Example 159
((S)-1-(4-fluorophenyl)-5,6-dimethyl-N-(2-phenylpropan-2-yl)-4,5-dihydro--
1H-indazole-5-carboxamide); Example 160
((S)-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)meth-
yl)aniline); Example 161
((S)-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)meth-
yl)-N-phenylacetamide); Example 162
((S)-N-ethyl-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-
-yl)methyl)aniline); Example 163
((S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
tert-butylcarbamate); Example 164
((S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
phenyl carbonate); Example 165
((S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
phenylcarbamate); Example 166
((S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
phenylcarbamate); Example 167
((S)-1-tert-butyl-3-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)methyl)urea); Example 168
((R,E)-1-(4-fluorophenyl)-5,6-dimethyl-5-styryl-4,5-dihydro-1H-indazole);
Example 169
((S)-5-(1,3-dioxolan-2-yl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazole); Example 170
((5S)-5-(4H-benzo[d][1,3]dioxin-2-yl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 171
((S)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-N-(1-
,3,4-thiadiazol-2-yl)propanamide); Example 172
((S)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-N-(t-
hiazol-2-yl)propanamide)); Example 173
((S)-N-(4,5-dimethylthiazol-2-yl)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazol-5-yl)propanamide); Example 174
((S)-3-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-N-
-(1,3,4-thiadiazol-2-yl)propanamide); Example 175
(5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1-
H-indazole); Example 176
(5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-6-((trimethyl-
silyl)ethynyl)-4,5-dihydro-1H-indazole); Example 177
(5-((R)-2-ethoxy-2-phenylethyl)-6-ethynyl-1-(4-fluorophenyl)-5-methyl-4,5-
-dihydro-1H-indazole); Example 178
(5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-6-phenyl-4,5--
dihydro-1H-indazole); Example 179
(5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1-
H-indazole-6-carbonitrile); Example 180
(6-chloro-5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5--
dihydro-1H-indazole); Example 181
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-ph-
enylethane-1,2-dione); Example 182
(1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-hy-
droxy-2-phenylethanone); Example 183
(1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-hy-
droxy-2-phenylethanone); Example 184
(2-(benzo[b]thiophen-3-yl)-1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazol-5-yl)propan-2-ol); Example 185
(2-(benzo[b]thiophen-3-yl)-1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazol-5-yl)propan-2-ol); Example 186
(1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-methyl-3-p-
henylbutan-1-ol); Example 187
(1-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3-met-
hyl-3-phenylbutan-1-ol); Example 188
(1-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3-met-
hyl-3-phenylbutan-1-ol); Example 189
(1-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3-phe-
nylpropan-1-ol); Example 190
(1-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3-phe-
nylpropan-1-ol); Example 191
(1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenylprop-
an-1-ol); Example 192
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-phenyl-
butan-2-ol); Example 193
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-methyl-
-4-phenylpentan-2-ol); Example 194
((S)-5-((4S,6S)-4,6-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)-5,6-dime-
thyl-4,5-dihydro-1H-indazole); Example 195
((S)-2,4-difluoro-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)methyl)benzamide); Example 196
((R)-5-((1,3-dioxolan-2-yl)methyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole); Example 197
((S)-5-((4R,5R)-4,5-dimethyl-1,3-dioxolan-2-yl)-1-(4-fluorophenyl)-5,6-di-
methyl-4,5-dihydro-1H-indazole); Example 198
((R,E)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1--
phenylprop-2-en-1-one); Example 199
(3-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-hy-
droxy-1-phenylpropan-1-one); Example 200
(3-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-hy-
droxy-1-phenylpropan-1-one); Example 201
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-ph-
enylethanone); Example 202
(1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenylprop-
an-1-one); Example 203
(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-phenylbuta-
n-2-ol); Example 204
(1,1,1-trifluoro-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5--
yl)-4-phenylbutan-2-ol); Example 205
(1-((S)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenyl-
propan-1-ol); Example 206
(1-((S)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl]-3-phenyl-
propan-1-ol); Example 207
(1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-methyl-3-p-
henylbutan-1-one); Example 208
(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-methyl-4-p-
henylpentan-2-ol); Example 209
(3-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-5-methyl-5-p-
henylhexan-3-ol); Example 210
((S)-1-tert-butyl-3-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol--
5-yl)methyl)urea); Example 211
((S)-1-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)--
3-(2-phenylpropan-2-yl)urea); Example 212
((S)-N-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)--
2-phenylacetamide); Example 213
((S)-N-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)--
1-phenylcyclopropanecarboxamide); Example 214
((S)-3-(2,4-difluorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-
-indazol-5-yl)propan-1-ol); Example 215
((S)-4-(2,4-difluorophenyl)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-
-indazol-5-yl)butan-2-ol); Example 216
((S)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-(3-met-
hoxyphenyl)propan-1-ol); Example 217
((S)-3-(4-chlorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-ind-
azol-5-yl)propan-1-ol); Example 218
((S)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-(3-met-
hoxyphenyl)butan-2-ol); Example 219
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-2-methyl-
-4-phenylbutan-2-ol); Example 220
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-2,4-dime-
thyl-4-phenylpentan-2-ol); Example 221
((S)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-(4-met-
hoxyphenyl)propan-1-ol); Example 222
((S)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-(4-met-
hoxyphenyl)butan-2-ol); Example 223
((R)-1-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-
-3-(2-phenylpropan-2-yl)urea); Example 224
((R)-1-tert-butyl-3-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazo-
l-5-yl)ethyl)urea); Example 225
((R)-N-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-
-1-phenylcyclopropanecarboxamide); Example 226
((R)-N-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-
thiazole-2-carboxamide); Example 227
((R)-N-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-imidazol-5-yl)ethyl-
)-2-phenylacetamide); Example 228
((S)-1-benzyl-3-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl-
)methyl)urea); Example 229
((S)-1-(2,4-difluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-
-indazol-5-yl)pentan-3-ol); Example 230
((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-4,5-dihydro-1H-indazole--
1-carboxamide); Example 231
((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-1-phenyl-4,5-dihydro-1H--
indazole); Example 232
((R)-5-((R)-2-ethoxy-2-phenylethyl)-1,5,6-trimethyl-4,5-dihydro-1H-indazo-
le); Example 233
(3-((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-1-yl)-N,N-dimethylbenzamide); Example 234
((5R)-1-(2,5-difluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole); or Example 235
((5R)-1-(2,4-difluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole); Example 236
((R)-1-(3-chloro-4-fluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 237
((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-1-(pyridin-2-yl)-4,5-dih-
ydro-1H-indazole); Example 238
((R)-1-(6-chloropyridazin-3-yl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimeth-
yl-4,5-dihydro-1H-indazole); Example 239
((5R)-5-((R)-2-ethoxy-2-phenylethyl)-1-(2-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); and Example 240
((R)-5-((R)-2-ethoxy-2-phenylethyl)-1-(3-fluorophenyl)-5,6-dimethyl-4,5-d-
ihydro-1H-indazole); or (ii) a pharmaceutically acceptable salt of
(i) thereof.
17. A compound according to claim 16 selected from: (i) Example 1
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-p-
henylethanol); Example 2
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-p-
henylethanol); Example 3
(1-(4-fluorophenyl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]ethanol); Example 4
(1-(4-fluorophenyl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]ethanol); Example 5
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-[-
4-(methyloxy)phenyl]ethanol); Example 7
(1-(4-fluorophenyl)-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]propan-2-ol); Example 8
(1-(4-fluorophenyl)-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazol-5-yl]propan-2-ol); Example 9
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]hex--
5-en-2-ol); Example 10
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]hex--
5-en-2-ol); Example 11
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-1-ylethanol); Example 12
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-1-ylethanol); Example 14
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-n-
aphthalen-2-ylethanol); Example 15
(1-biphenyl-2-yl-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]ethanol); Example 16
(1-biphenyl-2-yl-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]ethanol); Example 17
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
3-thienyl)ethanol); Example 18
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
3-thienyl)ethanol); Example 19
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
2-thienyl)ethanol); Example 20
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(-
2-thienyl)ethanol); Example 22
(1-(1-benzothien-3-yl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl]ethanol); Example 24
(2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-p-
henylethanone); Example 25
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-2-p-
henylpropan-2-o);1 Example 26
(1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-2-p-
henylpropan-2-ol); Example 27
(1,1,1-trifluoro-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]-2-phenylpropan-2-ol); Example 28
(1,1,1-trifluoro-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl]-2-phenylpropan-2-ol); Example 29
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-phenylethanol); Example 30
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-phenylethanol); Example 33
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-(2-thienyl)ethanol); Example 34
(2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-
-5-yl]-1-(2-thienyl)ethanol); Example 35
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-phenylethyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole); Example 36
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihy-
dro-1H-indazole); Example 37
((5R)-5-(2-(benzyloxy)-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 38
((5R)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-phenyl-2-propoxyethyl)-4,5-dih-
ydro- H-indazole); Example 39
((5R)-5-(2-(allyloxy)-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 40
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-ph-
enylethyl methylcarbamate); Example 41
((5R)-1-(4-fluorophenyl)-5-(2-isopropoxy-2-phenylethyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 42
((5R)-5-(2-cyclobutoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 43
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(naphthalen-1-yl)ethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 44
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(naphthalen-1-yl)ethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 45
((5R)-1-(4-fluorophenyl)-5-(2-(4-fluorophenyl)-2-methoxyethyl)-5,6-dimeth-
yl-4,5-dihydro-1H-indazole); Example 46
((5R)-5-(2-ethoxy-2-(4-fluorophenyl)ethyl)-1-(4-fluorophenyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole); Example 47
((5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-(2-methoxy-2-phenylethyl)-5-meth-
yl-4,5-dihydro-1H-indazole); Example 48
(1-(biphenyl-3-yl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazol-5-yl)ethanol); Example 49
(1-(biphenyl-3-yl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazol-5-yl)ethanol); Example 50
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-m--
tolylethanol); Example 51
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-m--
tolylethanol); Example 52
((5R)-5-(2-ethoxy-2-m-tolylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole); Example 53
(1-(3-fluorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 54
(1-(3-fluorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 55
((5R)-5-(2-ethoxy-2-(3-fluorophenyl)ethyl)-1-(4-fluorophenyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole); Example 56
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxyphenyl)ethanol); Example 57
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxyphenyl)ethanol); Example 58
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(2-methoxyphenyl)ethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 59
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-o--
tolylethanol); Example 60
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-o--
tolylethanol); Example 61
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole); Example 62
((5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole); Example 63
((5R)-5-(2-ethoxy-2-o-tolylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole); Example 65
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methoxyphenyl)ethanol); Example 66
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methoxyphenyl)ethanolv Example 67
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methylthiophen-2-yl)ethanol); Example 68
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-
-methylthiophen-2-yl)ethanol); Example 69
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(5-
-methylthiophen-2-yl)ethanol); Example 70
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(5-
-methylthiophen-2-yl)ethanol); Example 71
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(t-
hiazol-2-yl)ethanol); Example 72
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(t-
hiazol-2-yl)ethanol); Example 73
(1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)but-3-
-yn-2-ol); Example 74
(1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)but-3-
-yn-2-ol); Example 76
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-2-yl)ethanol); Example 77
((R)-5-(2-ethoxy-2-(pyridin-2-yl)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4-
,5-dihydro-1H-indazole); Example 78
(2-(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-
-hydroxyethyl)pyridine 1-oxide); Example 79
(2-(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-
-hydroxyethyl)pyridine 1-oxide); Example 80
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-3-yl)ethanol); Example 81
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(p-
yridin-3-yl)ethanol); Example 82
(1-(2,6-dimethylphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl)ethanol); Example 83
(1-(2,6-dimethylphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazol-5-yl)ethanol); Example 84
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methylnaphthalen-1-yl)ethanol); Example 85
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methylnaphthalen-1-yl)ethanol); Example 86
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxynaphthalen-1-yl)ethanol); Example 87
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-methoxynaphthalen-1-yl)ethanol); Example 89
(1-(2,6-dimethoxyphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazol-5-yl)ethanol); Example 90
(1-cyclopentyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)ethanol); Example 91
(1-cyclopentyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)ethanol); Example 95
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-
-(morpholinomethyl)phenyl)ethanol); Example 96
(1-(2-chlorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 97
(1-(2-chlorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazol-5-yl)ethanol); Example 98
((5R)-5-(2-(2-chlorophenyl)-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole); Example 99
((5R)-5-((1,3-dihydroisobenzofuran-1-yl)methyl)-1-(4-fluorophenyl)-5,6-di-
methyl-4,5-dihydro-1H-indazole); Example 100
((5R)-5-((1,3-dihydroisobenzofuran-1-yl)methyl)-1-(4-fluorophenyl)-5,6-di-
methyl-4,5-dihydro-1H-indazole); Example 101
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(4-
-methylthiazol-2-yl)ethanol); Example 102
(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(4-
-methylthiazol-2-yl)ethanol); Example 103
(2-(1-ethoxy-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)ethyl)-4-methylthiazole); Example 104
(2-(1-ethoxy-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)ethyl)-4-methylthiazole); Example 105
(1-cyclohexyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indaz-
ol-5-yl)ethanol); Example 106
(1-cyclohexyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indaz-
ol-5-yl)ethanol); Example 107
((5R)-5-(2-cyclohexyl-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 108
((5R)-5-(2-cyclohexyl-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); Example 116
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5,6,7--
tetrahydro-1H-indazole); Example 124
(((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-
-1H-indazol-6-yl)methanol); Example 127
(5R)-5-(2-ethoxy-2-phenylethyl)-6-ethyl-1-(4-fluorophenyl)-5-methyl-4,5-d-
ihydro-1H-indazole); Example 128
((5R)-6-(difluoromethyl)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5--
methyl-4,5-dihydro-1H-indazole); Example 132
(5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-in-
dazole); Example 137
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-6-methoxy-5-methyl-4,-
5-dihydro-1H-indazole); Example 140
((R)-5-(2-(benzyloxy)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-
H-indazole); Example 143
((R,E)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-(naphthalen-1-yl)vinyl)-4,5-d-
ihydro-1H-indazole); Example 145
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-ph-
enylethanol); Example 146
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-phenylpropan-1-ol); Example 148
((S)-1-(4-fluorophenyl)-5-((R)-1-methoxy-3-phenylpropyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole); Example 150
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-methyl-3-phenylbutan-1-ol); Example 151
((R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)--
3-methyl-3-phenylbutan-1-ol); Example 152
((S)-1-(4-fluorophenyl)-5-((R)-1-methoxy-3-methyl-3-phenylbutyl)-5,6-dime-
thyl-4,5-dihydro-1H-indazole); Example 153
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-me-
thyl-3-phenylbutan-1-one); Example 154
((S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylthiomethyl)-4,5-dihydro-1H--
indazole); Example 163
((S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
tert-butylcarbamate); Example 169
((S)-5-(1,3-dioxolan-2-yl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-
-indazole); Example 171
((S)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-N-(1-
,3,4-thiadiazol-2-yl)propanamide); Example 172
((S)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-N-(t-
hiazol-2-yl)propanamide)); Example 175
(5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1-
H-indazole); Example 177
(5-((R)-2-ethoxy-2-phenylethyl)-6-ethynyl-1-(4-fluorophenyl)-5-methyl-4,5-
-dihydro-1H-indazole); Example 179
(5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1-
H-indazole-6-carbonitrile); Example 180
(6-chloro-5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5--
dihydro-1H-indazole); Example 184
(2-(benzo[b]thiophen-3-yl)-1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazol-5-yl)propan-2-ol); Example 185
(2-(benzo[b]thiophen-3-yl)-1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazol-5-yl)propan-2-ol); Example 186
(1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-methyl-3-p-
henylbutan-1-ol); Example 191
(1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenylprop-
an-1-ol); Example 192
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-phenyl-
butan-2-ol); Example 193
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-methyl-
-4-phenylpentan-2-ol); Example 194
((S)-5-((4S,6S)-4,6-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)-5,6-dime-
thyl-4,5-dihydro-1H-indazole); Example 195
((S)-2,4-difluoro-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-inda-
zol-5-yl)methyl)benzamide); Example 196
((R)-5-((1,3-dioxolan-2-yl)methyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole); Example 197
((S)-5-((4R,5R)-4,5-dimethyl-1,3-dioxolan-2-yl)-1-(4-fluorophenyl)-5,6-di-
methyl-4,5-dihydro-1H-indazole); Example 198
((R,E)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1--
phenylprop-2-en-1-one); Example 199
(3-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-hy-
droxy-1-phenylpropan-1-one); Example 200
(3-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-hy-
droxy-1-phenylpropan-1-one); Example 201
((S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-ph-
enylethanone); Example 203
(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-phenylbuta-
n-2-ol); Example 204
(1,1,1-trifluoro-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5--
yl)-4-phenylbutan-2-ol); Example 205
(1-((S)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenyl-
propan-1-ol); Example 206
(1-((S)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenyl-
propan-1-ol); Example 211
((S)-1-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)--
3-(2-phenylpropan-2-yl)urea); Example 214
((S)-3-(2,4-difluorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-
-indazol-5-yl)propan-1-ol); Example 215
((S)-4-(2,4-difluorophenyl)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-
-indazol-5-yl)butan-2-ol); Example 218
((S)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-(3-met-
hoxyphenyl)butan-2-ol); Example 219
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-2-methyl-
-4-phenylbutan-2-ol); Example 220
((R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-2,4-dime-
thyl-4-phenylpentan-2-ol); Example 223
((R)-1-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-
-3-(2-phenylpropan-2-yl)urea); Example 229
((S)-1-(2,4-difluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-
-indazol-5-yl)pentan-3-ol); Example 231
((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-1-phenyl-4,5-dihydro-1H--
indazole); Example 234
((5R)-1-(2,5-difluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole); Example 235
((5R)-1-(2,4-difluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole); Example 236
((R)-1-(3-chloro-4-fluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimet-
hyl-4,5-dihydro-1H-indazole); Example 237
((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-1-(pyridin-2-yl)-4,5-dih-
ydro-1H-indazole); Example 239
((5R)-5-((R)-2-ethoxy-2-phenylethyl)-1-(2-fluorophenyl)-5,6-dimethyl-4,5--
dihydro-1H-indazole); and Example 240
((R)-5-((R)-2-ethoxy-2-phenylethyl)-1-(3-fluorophenyl)-5,6-dimethyl-4,5-d-
ihydro-1H-indazole); or (ii) a pharmaceutically acceptable salt of
(i) thereof.
18. A pharmaceutical composition comprising a compound as defined
in claim 1 and a pharmaceutically acceptable carrier therefor.
19. A method of treating an inflammatory or immune disease or
disorder comprising administering a pharmaceutically effective
amount of a compound of claim 1 wherein the disease or disorder is
selected from transplant rejection of kidney, liver, heart, lung,
pancreas, bone marrow, cornea, small bowel, skin allografts, skin
homografts, heart valve xenograft, serum sickness, and graft vs.
host disease, rheumatoid arthritis, psoriatic arthritis, multiple
sclerosis, Type I and Type II diabetes, juvenile diabetes, obesity,
asthma, inflammatory bowel disease, Crohn's disease, ulcerative
colitis, pyoderma gangrenum, systemic lupus erythematosis,
myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema,
seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's
disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's
or Sjorgen's syndrome, pernicious or immunohaemolytic anaemia,
atherosclerosis, Addison's disease, idiopathic adrenal
insufficiency, autoimmune polyglandular disease,
glomerulonephritis, scleroderma, morphea, lichen planus, viteligo,
alopecia greata, autoimmune alopecia, autoimmune hypopituatarism,
Guillain-Barre syndrome, and alveolitis; contact hypersensitivity,
delayed-type hypersensitivity, contact dermatitis, uticaria, skin
allergies, respiratory allergies, hayfever, allergic rhinitis and
gluten-sensitive enteropathy, osteoarthritis, acute pancreatis,
chronic pancreatitis, acute respiratory distress syndrome, Sezary's
syndrome, restenosis, stenosis and artherosclerosis, congenital
adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia
associated with cancer, juvenile rheumatoid arthritis, Ankylosing
spondylitis, acute and subacute bursitis, acute nonspecific
tenosynovitis, acute gouty arthritis, post-traumatic
osteroarthritis, synovitis of osteoarthritis, epicondylitis, acute
rheumatic carditis, pemphigus, bullous dermatitis herpetitformis,
severe erythema multiforme, exfoliative dermatitis, psoriasis,
seborrheic dermatitis, seasonal or perennial allergic rhinitis,
bronchial asthma, contact dermatitis, atopic dermatitis, drug
hypersensitivity reactions, allergic conjunctivitis, keratitis,
herpes zoster ophthalmicus, iritis and iridocyclitis,
chorioretinitis, optic neuritis, symptomatic sarcoidosis,
fulminating or disseminated pulmonary tuberculosis chemotherapy,
idiopathic thrombocytopenic purpura in adults, secondary
thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia,
leukemias and lymphomas in adults, acute leukemia of childhood,
ulcerative colitis, regional enteritis, Crohn's disease, Sjogren's
syndrome, autoimmune vasculitis, multiple sclerosis, myasthenia
gravis, sepsis, and chronic obstructive pulmonary disease.
20. The method as defined in claim 19 wherein the disease or
disorder is selected from transplant rejection, rheumatoid
arthritis, psoriatic arthritis, multiple sclerosis, Type I
diabetes, asthma, inflammatory bowel disease, systemic lupus
erythematosis, psoriasis, and chronic pulmonary disease.
Description
[0001] This application claims priority from U.S. Provisional
Application Ser. Nos. 60/690,355 and 60/782,636 filed Jun. 14, 2005
and Mar. 15, 2006, respectively.
FIELD OF THE INVENTION
[0002] The present invention relates to new non-steroidal compounds
which are effective modulators of the glucocorticoid receptor,
AP-1, and/or NF-.kappa.B activity and thus are useful in treating
diseases such as obesity, diabetes and inflammatory or immune
associated diseases, and to a method for using such compounds to
treat these and related diseases.
BACKGROUND OF THE INVENTION
[0003] The transcription factors NF-.kappa.B and AP-1 are involved
in regulating the expression of a number of genes involved in
mediating inflammatory and immune responses. NF-.kappa.B regulates
the transcription of genes including TNF-.alpha., IL-1, IL-2, IL-6,
adhesion molecules (such as E-selectin) and chemokines (such as
Rantes), among others. AP-1 regulates the production of the
cytokines TNF-.alpha., IL-1, IL-2, as well as, matrix
metalloproteases. Drug therapies targeting TNF-.alpha., a gene
whose expression is regulated by both NF-.kappa.B and AP-1, have
been shown to be highly efficacious in several inflammatory human
diseases including rheumatoid arthritis and Crohn's disease.
Accordingly, NF-.kappa.B and AP-1 play key roles in the initiation
and perpetuation of inflammatory and immunological disorders. See
Baldwin, A S, Journal of Clin. Investigation, 107, 3 (2001);
Firestein, G. S., and Manning, A. M., Arthritis and Rheumatism, 42,
609 (1999); and Peltz, G., Curr. Opin, in Biotech. 8, 467
(1997).
[0004] There are many signaling molecules (kinases and
phosphatases) upstream of AP-1 and NF-.kappa.B which are potential
therapeutic drug targets. The kinase JNK plays an essential role in
regulating the phosphorylation and subsequent activation of c-jun,
one of the subunits which constitute the AP-1 complex (fos/c-jun).
Compounds which inhibit JNK have been shown to be efficacious in
animal models of inflammatory disease. See Manning A M and Davis R
J, Nature Rev. Drug Disc., V. 2, 554 (2003). A kinase critical to
the activation of NF-.kappa.B is the I.kappa.B kinase (IKK). This
kinase plays a key role in the phosphorylation of I.kappa.B. Once
I.kappa.B is phosphorylated it undergoes degradation leading to the
release of NF-.kappa.B which can translocate into the nucleus and
activate the transcription of the genes described above. An
inhibitor of IKK, BMS-345541, has been shown to be efficacious in
animal models of inflammatory disease. See Burke J R., Curr Opin
Drug Discov Devel., September; 6(5), 720-8, (2003).
[0005] In addition to inhibiting signaling cascades involved in the
activation of NF-.kappa.B and AP-1, the glucocorticoid receptor has
been shown to inhibit the activity of NF-.kappa.B and AP-1 via
direct physical interactions. The glucocorticoid receptor (GR) is a
member of the nuclear hormone receptor family of transcription
factors, and a member of the steroid hormone family of
transcription factors. Affinity labeling of the glucocorticoid
receptor protein allowed the production of antibodies against the
receptor which facilitated cloning the glucocorticoid receptors.
For results in humans see Weinberger, et al., Science 228, 640-742,
(1985); Weinberger, et al., Nature, 318, 670-672 (1986) and for
results in rats see Miesfeld, R., Nature, 312, 779-781, (1985).
[0006] Glucocorticoids which interact with GR have been used for
over 50 years to treat inflammatory diseases. It has been clearly
shown that glucocorticoids exert their anti-inflammatory activity
via the inhibition by GR of the transcription factors NF-.kappa.B
and AP-1. This inhibition is termed transrepression. It has been
shown that the primary mechanism for inhibition of these
transcription factors by GR is via a direct physical interaction.
This interaction alters the transcription factor complex and
inhibits the ability of NF-.kappa.B and AP-1 to stimulate
transcription. See Jonat, C., et al., Cell, 62, 1189 (1990);
Yang-Yen, H. F., et al., Cell, 62, 1205 (1990); Diamond, M. I., et
al., Science 249, 1266 (1990); and Caldenhoven, E,. et al., Mol.
Endocrinol., 9, 401 (1995). Other mechanisms such as sequestration
of co-activators by GR have also been proposed. See Kamer Y., et
al., Cell, 85, 403 (1996); and Chakravarti, D., et al., Nature,
383, 99 (1996).
[0007] In addition to causing transrepression, the interaction of a
glucocorticoid with GR can cause GR to induce transcription of
certain genes. This induction of transcription is termed
transactivation. Transactivation requires dimerization of GR and
binding to a glucocorticoid response element (GRE).
[0008] Recent studies using a transgenic GR dimerization defective
mouse which cannot bind DNA have shown that the transactivation
(DNA binding) activities of GR could be separated from the
transrepressive (non-DNA binding) effect of GR. These studies also
indicate that many of the side effects of glucocorticoid therapy
are due to the ability of GR to induce transcription of various
genes involved in metabolism, whereas, transrepression, which does
not require DNA binding leads to suppression of inflammation. See
Tuckermann, J. et al., Cell, 93, 531 (1998) and Reichardt, H M,
EMBO J., 20, 7168 (2001).
[0009] PCT application WO 2004/009017 published Jan. 29, 2004,
assigned to Applicant and incorporated herein by reference in its
entirety, describes substituted bicyclooctane compounds useful in
treating diseases such as obesity, diabetes and inflammatory or
immune associated diseases.
[0010] In addition, a number of patent applications, including WO
03/086294 and WO04/075840, published Oct. 23, 2003 and Sep. 10,
2004, respectively, both assigned to Merck and Co., Inc, as well as
WO 03/061651, published Jul. 31, 2003 and assigned to The Regents
of the U. of CA, describe compounds having a fused tricyclic ring
system that are said to be useful in treating diseases associated
with binding to the glucocorticoid receptor, including autoimmune
and inflammatory diseases and conditions.
[0011] Compounds that modulate AP-1 and/or NF-.kappa.B activity
would be useful as such compounds would be useful in the treatment
of inflammatory and immune diseases and disorders such as
osteoarthritis, rheumatoid arthritis, multiple sclerosis, asthma,
inflammatory bowel disease, transplant rejection and graft vs. host
disease.
[0012] Also, with respect to the glucocorticoid receptor pathway,
it is known that glucocorticoids are potent anti-inflammatory
agents, however their systemic use is limited by side effects.
Compounds that retain the anti-inflammatory efficacy of
glucocorticoids while minimizing the side effects such as diabetes,
osteoporosis and glaucoma would be of great benefit to a very large
number of patients with inflammatory diseases.
[0013] Additionally concerning GR, the art is in need of compounds
that antagonize transactivation. Such compounds may be useful in
treating metabolic diseases associated with increased levels of
glucocorticoid, such as diabetes, osteoporosis and glaucoma.
[0014] Additionally concerning GR, the art is in need of compounds
that cause transactivation. Such compounds may be useful in
treating metabolic diseases associated with a deficiency in
glucocorticoid. Such diseases include Addison's disease.
[0015] Also, there is a need for new compounds with improved
activity compared with known modulators of GR, AP-1, and/or
NF-.kappa.B activity. It is also desirable and preferable to find
compounds with advantageous and improved characteristics in one or
more categories, which may be, but are not limited to, the
following: (a) pharmaceutical properties; (b) dosage requirements;
(c) factors which decrease blood concentration peak-to-trough
characteristics; (d) factors that increase the concentration of
active drug at the receptor; (e) factors that decrease the
liability for clinical drug-drug interactions; (f) factors that
decrease the potential for adverse side-effects; (g) factors that
improve manufacturing costs or feasibility and (h) factors leading
to desirable physical characteristics.
DESCRIPTION OF THE INVENTION
[0016] The present invention relates to new non-steroidal compounds
which are which are particularly effective modulators of the
glucocorticoid receptor, AP-1, and/or NF-.kappa.B activity and thus
are useful in treating diseases such as obesity, diabetes and
inflammatory or immune associated diseases, and to a method and
composition for using such compounds to treat these and related
diseases.
[0017] In accordance with the present invention, compounds are
provided having the structure of formula (I) ##STR2## or an
enantiomer, a diastereomer, or a pharmaceutically acceptable salt
thereof,
[0018] wherein: [0019] is a single or double bond; [0020] A is a
partially saturated ring; [0021] n is 0, 1, or 2; [0022] J is
NR.sub.1 or C(R.sub.4)(R.sub.4a); [0023] K is NR.sub.2 or
C(R.sub.5)(R.sub.5a); [0024] L is NR.sub.3 or C(R.sub.6)(R.sub.6a);
[0025] X is a bond, alkylene, alkenylene, alkynylene, --C(O),
--N(R.sub.14)--, --N(R.sub.14)alkylene-, --Oalkylene-,
--N(R.sub.14)--C(O)--, --N(R.sub.14)--C(O)O--,
--NR.sub.15C(O)NR.sub.16, --S(O).sub.t-- ##STR3## [0026] Y is
selected from hydrogen, halogen, nitro, cyano; OR.sub.12,
NR.sub.12R.sub.13, C(.dbd.O)R.sub.12, CO.sub.2R.sub.12,
C(.dbd.O)NR.sub.12R.sub.13, O--C(.dbd.O)NR.sub.12R.sub.13,
--O--C(.dbd.O)R.sub.12, NR.sub.12C(.dbd.O)R.sub.13,
NR.sub.12C(O)OR.sub.13, NR.sub.12C(O)N(R.sub.13).sub.2,
NR.sub.12C(S)OR.sub.13, S(O).sub.pR.sub.20,
NR.sub.12S(O).sub.pN(R.sub.13).sub.2, NR.sub.12S(O).sub.pR.sub.20,
and S(O).sub.pNR.sub.12R.sub.13; or [0027] Y is taken together with
R.sub.8 to form an oxo, a substituted alkenyl, or an unsubstituted
alkenyl; [0028] R.sub.1 is selected from (i) alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
OR.sub.14, NR.sub.14S(O).sub.pR.sub.21, cycloalkyl, heterocyclo,
aryl, and heteroaryl; and/or (ii) R.sub.1 is taken together with
R.sub.2 or R.sub.2 is taken together with R.sub.3 to form a double
bond; [0029] R.sub.2, and R.sub.3 are independently selected from
(i) hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, OR.sub.14,
NR.sub.14S(O).sub.pR.sub.21, cycloalkyl, heterocyclo, aryl, and
heteroaryl; and/or (ii) R.sub.1 is taken together with R.sub.2 or
R.sub.2 is taken together with R.sub.3 to form a double bond;
[0030] R.sub.4, R.sub.4a, R.sub.5, R.sub.5a, R.sub.6, and R.sub.6a
are independently selected from (i) hydrogen, halogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, nitro, azide, cyano, OR.sub.15,
NR.sub.15R.sub.16, C(.dbd.O)R.sub.15, CO.sub.2R.sub.15,
C(.dbd.O)NR.sub.15R.sub.16, O--C(.dbd.O)NR.sub.12R.sub.13,
--O--C(.dbd.O)R.sub.15, NR.sub.15C(.dbd.O)R.sub.16,
NR.sub.15C(O)OR.sub.16, NR.sub.15C(S)OR.sub.16, S(O).sub.qR.sub.22,
NR.sub.15S(O).sub.qR.sub.22, S(O).sub.qNR.sub.15R.sub.16,
cycloalkyl, heterocyclo, aryl, and heteroaryl; and/or (ii) R.sub.4
may be taken together with R.sub.4a, and/or R.sub.5 may be taken
together with R.sub.5a, and/or R.sub.6 may be taken together with
R.sub.6a to form an oxo, alkenyl, or substituted alkenyl group;
and/or (iii) each one of R.sub.4, R.sub.4a, R.sub.5, R.sub.5a,
R.sub.6, and R.sub.6a is taken together with any one of R.sub.4,
R.sub.4,R.sub.5, R.sub.5a, R.sub.6, and R.sub.6a located on an
adjacent carbon atom to form a double bond or a fused ring; [0031]
or when J is NR.sub.2, and/or K is NR.sub.2, and/or L is NR.sub.3,
each one of R.sub.1, R.sub.2, and/or R.sub.3 is taken together with
one of R.sub.4, R.sub.4a, R.sub.5, R.sub.5a, R.sub.6, and R.sub.6a
which is located on an adjacent carbon atom to form a double bond;
[0032] R.sub.8 and R.sub.10 are independently selected from (i)
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, OR.sub.17, S(O).sub.rR.sub.23,
NR.sub.17S(O).sub.rR.sub.23, cycloalkyl, heterocyclo, aryl, and
heteroaryl; or (ii) R.sub.8 is taken together with R.sub.10 to form
a cycloalkyl, heterocyclo, aryl, and heteroaryl ring; and/or (iii)
R.sub.8 is taken together with Y to form an oxo, alkenyl, or a
substituted alkenyl group; [0033] R.sub.11 at each occurrence is
independently selected from (i) alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, halogen, nitro,
azide, cyano, OR.sub.19, cycloalkyl,-heterocyclo, aryl, and
heteroaryl; and/or (ii) two R.sub.1 groups located on the same
carbon atom are taken together to form an oxo, alkenyl, or a
substituted alkenyl group; [0034] R.sub.12, R.sub.13, R.sub.14,
R.sub.15, R.sub.16, R.sub.17, R.sub.18, and R.sub.19 at each
occurrence are independently selected from (i) hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) R.sub.12 is taken together with R.sub.13 and/or R.sub.15 is
taken together with R.sub.16 to form a heteroaryl or heterocyclo
ring; [0035] R.sub.20, R.sub.21, R.sub.22, and R.sub.23 are
independently selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; and [0036] p, q, r and t are
independently selected from 0, 1 and 2.
[0037] Preferred embodiments of the compounds are within the scope
of formula (I) and are described in paragraphs 1-14, below. Aspects
of each embodiment may be combined with other embodiments to form
other preferred embodiments.
[0038] 1. A compound, or an enantiomer, a diastereomer, a
pharmaceutically acceptable salt, or hydrate thereof, wherein J is
NR.sub.1; K is NR.sub.2; L is C(R.sub.6)(R.sub.6a); and R.sub.2 and
R.sub.6a are joined together to form a double bond.
[0039] 2. A compound, within the scope of embodiment 1, or an
enantiomer, a pharmaceutically acceptable salt, or hydrate thereof,
wherein an optional double bond shown in ring A of the compound of
Formula I is present.
[0040] 3. A compound, within the scope of embodiments 1 or 2, or an
enantiomer, a diastereomer, a pharmaceutically acceptable salt, or
hydrate thereof, wherein: [0041] R.sub.1 is cycloalkyl, aryl,
heterocyclo, or heteroaryl, said cycloalkyl, aryl, heterocyclo, or
heteroaryl is substituted with from one up to the maximum number of
substitutable positions with a substituent independently selected
from hydrogen, halogen, nitro, cyano, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl,
C.sub.2-6alkynyl, substituted C.sub.2-6alkynyl, OR.sub.a,
C(.dbd.O)NR.sub.aR.sub.b, C(.dbd.O)R.sub.a, CO.sub.2R.sub.a,
O--C(.dbd.O)NR.sub.aR.sub.b, C(.dbd.O)NR.sub.aR.sub.b,
--O--C(.dbd.O)R.sub.a, NR.sub.aC(.dbd.O)R.sub.b,
NR.sub.aC(O)OR.sub.b, NR.sub.8C(S)OR.sub.b, S(O).sub.sR.sub.c,
NR.sub.aS(O).sub.sR.sub.c, S(O).sub.pNR.sub.aR.sub.b, cycloalkyl,
heterocyclo, aryl, and heteroaryl; [0042] R.sub.a and R.sub.b at
each occurrence are independently selected from (i) hydrogen,
alkyl,, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) R.sub.a is taken together with R.sub.b to form a heteroaryl
or heterocyclo ring; [0043] R.sub.c is selected from alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
and [0044] s is 1 or 2.
[0045] More preferably, R.sub.1 is aryl or heteroaryl, each of
which is substituted with 1-3 groups selected from hydrogen,
halogen, nitro, cyano, C.sub.1-6alkyl, substituted C.sub.1-6alkyl,
OR.sub.a, NR.sub.aR.sub.b, C(.dbd.O)NR.sub.aR.sub.b, S(O),W,
NR.sub.aS(O).sub.sR.sub.c, S(O).sub.pNR.sub.aR.sub.b, and
C.sub.3-7cycloalkyl. Even more preferably, R.sub.1 is aryl (e.g.
phenyl, napthyl, etc.) or a nitrogen containing heteroaryl (e.g.
pyridyl, pyradizinyl, etc.)substituted by 1-3 groups selected from
hydrogen, halogen, amido, cyano, nitro, trifluoromethyl, or
C.sub.1-4alkyl (particularly where R.sub.1 is phenyl substituted by
1-2 halogens, preferably fluoro).
[0046] 4. A compound within the scope of embodiments 1, 2, or 3, or
an enantiomer, a diastereomer, a pharmaceutically acceptable salt,
or hydrate thereof, wherein: [0047] X is a bond, alkylene,
--N(R.sub.14)--, --N(R.sub.14)alkylene-, --N(R.sub.14)C(O)--,
--Oalkylene-, --NR.sub.15C(O)NR.sub.16--, --S(O).sub.t--,
--OC(O)NH--, or --OC(O)O-- (preferably X is a bond, alkylene, or
--N(R.sub.14)C(O)--); [0048] Y is (i) hydrogen, OR.sub.12,
NR.sub.12R.sub.13, or O--C(.dbd.O)NR.sub.12R.sub.13; or (ii) Y
together with R.sub.8 combines to form oxo or alkenyl (preferably Y
is (i) hydrogen or OR.sub.12; or (ii) Y is taken together with
R.sub.8 to form oxo); [0049] R.sub.8 is (i) hydrogen, alkyl,
substituted alkyl; or (ii) R.sub.8 together with Y forms oxo or
alkenyl; or (iii) R.sub.8 together with R.sub.10 combines to form
heterocyclo (preferably R.sub.8 is (i) hydrogen, alky or
substituted alkyl; or (ii) R.sub.8 is taken together with Y to form
oxo); [0050] R.sub.10 is (i) hydrogen, hydroxy, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted
alkynyl; or (ii) cycloalkyl, aryl, heterocyclo, or heteroaryl;
wherein said cycloalkyl, aryl, heterocyclo, or heteroaryl is
optionally substituted with from one up to the maximum number of
substitutable positions with a substituent independently selected
from the group consisting of halogen, nitro, cyano, C.sub.1-6alkyl,
oxo, N-oxide, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl, substituted
C.sub.2-6alkynyl, OR.sub.d, NR.sub.dR.sub.e, C(.dbd.O)R.sub.d,
CO.sub.2R.sub.d, --O--C(.dbd.O)NR.sub.dR.sub.e,
C(.dbd.O)NR.sub.dR.sub.e, --O--C(.dbd.O)R.sub.d,
NR.sub.dC(.dbd.O)R.sub.d, N.sub.dC(O)OR.sub.e,
NR.sub.dC(S)OR.sub.e, S(O).sub.vR.sub.f, NR.sub.dS(O).sub.vR.sub.f,
S(O).sub.vNR.sub.dR.sub.e, cycloalkyl, heterocyclo, aryl, and
heteroaryl (preferably R.sub.10 is cycloalkyl, heterocyclo, aryl or
heteroaryl, each group of which is optionally substituted); [0051]
R.sub.d and R.sub.e at each occurrence are independently selected
from (i) hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl,
heteroaryl, and heterocyclo; and/or (ii) R.sub.d is taken together
with R.sub.e to form a heteroaryl or heterocyclo ring; [0052]
R.sub.f is selected from hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl, and heterocyclo; and [0053] v is 1 or
2.
[0054] 5. A compound, within the scope of embodiments 1, 2, 3 or 4,
or an enantiomer, a diastereomer, a pharmaceutically acceptable
salt, or hydrate thereof, wherein [0055] X is a bond, alkylene,
alkenylene, alkynylene, --C(O), --N(R.sub.14)--,
--N(R.sub.14)--C(O)--, or ##STR4## [0056] Y is selected from
hydrogen, halogen, nitro, cyano; OR.sub.12, NR.sub.12R.sub.13,
C(.dbd.O)R.sub.12, CO.sub.2R.sub.12, C(.dbd.O)NR.sub.12R.sub.13,
O--C(.dbd.O)NR.sub.12R.sub.13, --O--C(.dbd.O)R.sub.12,
NR.sub.12C(.dbd.O)R.sub.13, NR.sub.12C(O)OR.sub.13,
NR.sub.12C(S)OR.sub.13, S(O).sub.pR.sub.20,
NR.sub.12S(O).sub.pN(R.sub.13).sub.2, NR.sub.12S(O).sub.pR.sub.20,
and S(O).sub.pNR.sub.12R.sub.13; [0057] R.sub.8 and R.sub.10 are
independently selected from (i) hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
OR.sub.17, S(O).sub.rR.sub.23, NR.sub.17S(O).sub.rR.sub.23,
cycloalkyl, heterocyclo, aryl, and heteroaryl; or (ii) R.sub.8 may
be taken together with R.sub.10 to form a ring; [0058] R.sub.11 at
each occurrence is independently selected from alkyl, substituted
alkyl, alkenyl, substituted alkenyl, halogen, cyano, nitro,
OR.sub.19, cycloalkyl, heterocyclo, aryl, and heteroaryl; and
[0059] p, q, and r are independently selected from 1 and 2.
[0060] 6. A compound, within the scope of embodiments 1, 2, 3, 4,
or 5, having formula II: ##STR5## or an enantiomer, a diastereomer,
or a pharmaceutically acceptable salt thereof.
[0061] 7. A compound, within the scope of embodiments 1, 2, 3, 4,
5, or 6, or an enantiomer, a diastereomer, a pharmaceutically
acceptable salt, or hydrate thereof, wherein [0062] X is a (i) a
bond, alkylene, --N(R.sub.14)--, --N(R.sub.14)alkylene-,
--N(R.sub.14)C(O)--, --Oalkylene-, --NR.sub.15C(O)NR.sub.16--,
--S(O).sub.t--, --OC(O)N(R.sub.14)--, or --OC(O)O-- (X is
preferably a bond or --C(.dbd.O)N(R.sub.14)--; [0063] Y is (i)
hydrogen, OR.sub.12, NR.sub.12R.sub.13, or
O--C(--O)NR.sub.12R.sub.13; or (ii) Y is taken together with
R.sub.8 to form oxo or alkenyl (Y is preferably (i) OR.sub.12; or
(ii) Y is taken together with R.sub.8 to form oxo); [0064] R.sub.1
is aryl substituted with 1-3 groups selected from hydrogen,
halogen, nitro, cyano, C.sub.1-6alkyl, substituted C.sub.1-6alkyl,
OR.sub.a, NR.sub.aR.sub.b, C(.dbd.O)NR.sub.aR.sub.b,
S(O).sub.sR.sub.c, NR.sub.aS(O).sub.sR.sub.c,
S(O).sub.pNR.sub.aR.sub.b, and C.sub.3-7cycloalkyl; R.sub.8 is (i)
hydrogen, C.sub.1-6alkyl, or substituted C.sub.1-6alkyl; or (ii)
R.sub.8 is taken together with Y to form oxo or alkenyl; or (iii)
R.sub.8 is combined with R.sub.10 to form a heterocyclo; [0065]
R.sub.10 is (i) hydrogen, hydroxy, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or
(ii) cycloalkyl, aryl, heterocyclo, or heteroaryl; said cycloalkyl,
aryl, heterocyclo, or heteroaryl optionally substituted with from
one up to the maximum number of substitutable positions with
substituents independently selected from halogen, nitro, cyano,
C.sub.1-6alkyl, oxo, N-oxide, substituted C.sub.1-6alkyl,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl,
substituted C.sub.2-6alkynyl, OR.sub.d, NR.sub.dR.sub.e,
C(.dbd.O)R.sub.d, CO.sub.2R.sub.d, --O--C(--O)NR.sub.dR.sub.e,
C(.dbd.O)NR.sub.dR.sub.e, --O--C(.dbd.O)R.sub.d,
NR.sub.dC(.dbd.O)R.sub.e, NR.sub.dC(O)OR.sub.e,
NR.sub.dC(S)OR.sub.e, S(O).sub.vR.sub.f, NR.sub.dS(O).sub.vR.sub.f,
S(O),NR.sub.dR.sub.e, cycloalkyl, heterocyclo, aryl, and heteroaryl
(preferably R.sub.10 is cycloalkyl, heterocyclo, aryl or
heteroaryl; said cycloalkyl, heterocyclo, aryl or heteroaryl
optionally substituted with one substituent chosen from halogen,
CN, NR.sub.dR.sub.e, N-oxide, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl (especially substituted methylene), OH,
OC.sub.1-6alkyl, OCF.sub.3, CF.sub.3, phenyl, pyrrolyl,
morpholinyl, --O (optionally substituted phenyl), or --O
(optionally substituted benzyl)); or (iii) R.sub.8 is combined with
R.sub.10 to form benozdioxinyl or dioxolanyl); [0066] each R.sub.11
is (i) independently selected from hydrogen, halogen, cyano, nitro,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, cycloalkyl, OR.sub.19,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, and
C.sub.3-6cycloalkyl; and/or (ii) two R.sub.11 groups located on the
same carbon atom are taken together to form an oxo group; [0067]
R.sub.12 and R.sub.13 are independently selected from hydrogen,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl, substituted
C.sub.2-6alkynyl, C.sub.3-7 cycloalkyl, C.sub.2-6alkenyl, or
acetyl; [0068] R.sub.a, R.sub.b, R.sub.d and R.sub.e at each
occurrence are independently selected from (i) hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) R.sub.a is taken together with R.sub.b and/or R.sub.d is
taken together with R.sub.e to form a heteroaryl or heterocyclo
ring; [0069] R.sub.e and R.sub.f at each occurrence are
independently selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
aryl, heteroaryl, and heterocyclo; and [0070] v is 1 or 2.
[0071] 8. A compound within the scope of embodiments 1, 2, 3, 4, 5,
6 or 7, an enantiomer, a diastereomer, a pharmaceutically
acceptable salt, or hydrate thereof, wherein: [0072] n is 0 or 1;
[0073] X is a (i) a bond; or (ii) C.sub.1-4alkylene or
C.sub.2-4alkenylene, each of which is substituted with one to three
groups selected from hydrogen, halogen, OH, OCH.sub.3, and
OCF.sub.3; [0074] Y is OR.sub.12; [0075] R.sub.8 is (i) hydrogen,
C.sub.1-6alkyl, or substituted C.sub.1-6alkyl; or (ii) R.sub.8 is
combined with Y to form .dbd.O; [0076] R.sub.10 is selected from
the group consisting of: (i) hydroxy, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl,
C.sub.2-6alkynyl, substituted C.sub.2-6alkynyl, and
C.sub.3-6cycloalkyl; or (ii) phenyl, phenylsulfonyl, napthyl,
quinolinyl, pyrrolyl, pyridyl, thiazolyl, benzothiazolyl, thienyl,
benzothienyl, furyl, and benzofuryl, each group of which is
optionally further substituted by one up to the maximum number of
substitutable positions with a substituent independently selected
from halogen, CN, NR.sub.dR.sub.e, C.sub.1-6alkyl, OH,
OC.sub.1-6alkyl, OCF.sub.3, CF.sub.3, --O (optionally substituted
phenyl), or --O (optionally substituted benzyl); [0077] R.sub.d and
R.sub.e are independently selected (i) from hydrogen,
C.sub.1-6alkyl, and substituted C.sub.1-6alkyl; or (ii) R.sub.d is
taken together with R.sub.e to form a heteroaryl or heterocyclo
ring; [0078] each R.sub.11 is independently selected from
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
substituted C.sub.2-6alkenyl, and C.sub.3-6cycloalkyl; and [0079]
R.sub.12 is hydrogen or C.sub.1-6alkyl.
[0080] 9. A compound within the scope of embodiments 1, 2, 3, 4, 5,
6, or 7, an enantiomer, a diastereomer, a pharmaceutically
acceptable salt, or hydrate thereof, having formula III: ##STR6##
wherein: [0081] R.sub.1 is phenyl substituted with 1-3 groups
selected from halogen, nitro, cyano, methyl, methoxy, ethoxy,
nitro, cyano, and CF.sub.3, particularly where the substituents are
one to two halogens, especially fluoro; [0082] R.sub.11b and
R.sub.11c are independently selected from hydrogen, halogen, nitro,
cyano, C.sub.1-6alkyl, substituted C.sub.1-6alkyl,
C.sub.2-6alkenyl, substituted C.sub.2-6alkenyl, and
C.sub.3-7cycloalkyl.
[0083] 10. A compound within the scope of embodiments 1, 2, 3, 4,
5, 6, 7 and 9, an enantiomer, a diastereomer, a pharmaceutically
acceptable salt, or hydrate thereof, wherein: [0084] X is a bond,
alkylene, or --N(R.sub.14)--; [0085] Y is (i) hydrogen or
OR.sub.12; or (ii) Y is taken together with R.sub.8 to form oxo;
[0086] R.sub.8 is (i) hydrogen, CF.sub.3, or CH.sub.3; or (ii)
R.sub.8 is taken together with Y to form oxo. [0087] R.sub.10 is
selected from the group consisting of: (i) hydrogen, hydroxy,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
substituted C.sub.2-6alkenyl, C.sub.2-6alkynyl, substituted
C.sub.2-6alkynyl, and C.sub.3-6cycloalkyl; or (ii) cyclopentyl,
cyclohexyl, phenyl, phenylsulfonyl, napthyl, quinolinyl, pyrrolyl,
pyridyl, thiazolyl, thiadiazolyl, benzothiazolyl, thienyl,,
benzothienyl, furyl, 1,3-dihydroisobenzofuryl, and benzofuryl, each
group of which is optionally further substituted by one up to the
maximum number of substitutable positions with a substituent
independently selected from halogen, CN, N.sub.dR.sub.e, N-oxide,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, OH, OC.sub.1-6alkyl,
OCF.sub.3, CF.sub.3, phenyl, pyrrolyl, morpholinyl, --O (optionally
substituted phenyl), or --O (optionally substituted benzyl); or
(iii) R.sub.8 is combined with R.sub.10 to form benozdioxinyl or
dioxolanyl; and [0088] R.sub.14 is selected from hydrogen,
C.sub.1-6alkyl, and --C(O)C.sub.1-6alkyl; [0089] v is 1 or 2.
[0090] 11. Compounds within the scope of embodiments 1-7 and 9-10,
an enantiomer, a diastereomer, a pharmaceutically acceptable salt,
or hydrate thereof, wherein: [0091] X is a bond, methylene,
ethylene, butylene, or --N(R.sub.14)--; [0092] R.sub.12 and
R.sub.13 are independently selected from hydrogen, C.sub.1-6alkyl,
substituted C.sub.1-6alkyl, acetyl, C.sub.2-6alkenyl, and
--OC(O)NHC.sub.1-6alkyl; [0093] R.sub.14 is selected from hydrogen,
ethyl, and --C(O)Me; [0094] R.sub.d and R.sub.e are independently
(i) hydrogen, C.sub.1-6alkyl, or substituted C.sub.1-6alkyl; or
(ii) R.sub.d is taken together with R.sub.e to form a heteroaryl or
heterocyclo ring; [0095] R.sub.f is selected from hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo;
and [0096] v is 1 or 2.
[0097] 12. Compounds within the scope of embodiments 1-7 and 9-11,
of formula (IV): ##STR7## or an enantiomer, a diastereomer, or a
pharmaceutically acceptable salt thereof.
[0098] 13. Compounds within the scope of embodiments 1-7 and 9-12,
or an enantiomer, a diastereomer, or a pharmaceutically acceptable
salt thereof, wherein: [0099] X is a bond; [0100] Y is
--OC.sub.1-6alkyl or --OC.sub.2-6alkenyl; [0101] R.sub.8 is
hydrogen; [0102] R.sub.10 is an optionally substituted phenyl
group; [0103] R.sub.11b is C.sub.1-6alkyl; and [0104] n is 1.
[0105] 14. Compounds within the scope of embodiments 1-7 and 9-12,
or an enantiomer, a diastereomer, or a pharmaceutically acceptable
salt thereof, wherein: [0106] X is --NH--; [0107] Y is taken
together with R.sub.8 to form oxo; [0108] R.sub.10 is an optionally
substituted five-membered heteroaryl group; [0109] R.sub.11b is
C.sub.1-6alkyl; and [0110] n is 2.
[0111] In another embodiment of the present invention, there is
provided pharmaceutical compositions useful in treating endocrine
disorders, rheumatic disorders, collagen diseases, dermatologic
disease, allergic disease, ophthalmic disease, respiratory disease,
hematologic disease, gastrointestinal disease, inflammatory
disease, autoimmune disease, diabetes, obesity, and neoplastic
disease (especially inflammatory and autoimmune disease), as well
as other uses as described herein, which includes a therapeutically
effective amount (depending upon use) of a compound of formula (I)
of the invention and a pharmaceutically acceptable carrier.
[0112] In still another embodiment, the present invention provides
a method of treating endocrine disorders, rheumatic disorders,
collagen diseases, dermatologic disease, allergic disease,
ophthalmic disease, respiratory disease, hematologic disease,
gastrointestinal disease, inflammatory disease, autoimmune disease,
diabetes, obesity, and neoplastic disease (especially inflammatory
and autoimmune disease), that is a disease associated with the
expression product of a gene whose transcription is stimulated or
repressed by glucocorticoid receptors, or a disease associated with
AP-1- and/or NF.kappa.B (particularly AP-1-)-induced transcription,
or a disease associated with AP-1 and/or NF.kappa.B-- (particularly
AP-1-) dependent gene expression, wherein the disease is associated
with the expression of a gene under the regulatory control of AP-1
and/or NF-.kappa.B (particularly AP-1), including inflammatory and
immune diseases and disorders as described hereinafter, which
includes the step of administering a therapeutically effective
amount of a compound of formula (I) of the invention to a
patient.
[0113] Another embodiment of the present invention involves a
method for treating a disease or disorder associated with the
expression product of a gene whose transcription is stimulated or
repressed by glucocorticoid receptors, or a method of treating a
disease or disorder associated with AP-1- and/or NF-.kappa.B--
(particularly AP-1-) induced transcription, or a method for
treating a disease or disorder associated with AP-1 and/or
NF-.kappa.B (particularly AP-1) dependent gene expression, wherein
the disease is associated with the expression of a gene under the
regulatory control of AP-1 and/or NF-.kappa..beta. (particularly
AP-1), such as inflammatory and immune disorders, cancer and tumor
disorders, such as solid tumors, lymphomas and leukemia, and fungal
infections such as mycosis fungoides (especially inflammatory and
immune disorders).
[0114] The term "disease associated with GR transactivation," as
used herein, refers to a disease associated with the transcription
product of a gene whose transcription is transactivated by a GR.
Such diseases include, but are not limited to: osteoporosis,
diabetes, glaucoma, muscle loss, facial swelling, personality
changes, hypertension, obesity, depression, and AIDS, the condition
of wound healing, primary or secondary andrenocortical
insufficiency, and Addison's disease.
[0115] The term "treat", "treating", or "treatment," in all
grammatical forms, as used herein refers to the prevention,
reduction, or amelioration, partial or complete alleviation, or
cure of a disease, disorder, or condition, wherein prevention
indicates treatment of a person at risk for developing such a
disease, disorder or condition.
[0116] The terms "glucocorticoid receptor" and "GR," as used
herein, refer either to a member of the nuclear hormone receptor
("NHR") family of transcription factors which bind glucocorticoids
and either stimulate or repress transcription, or to GR-beta. These
terms, as used herein, refer to glucocorticoid receptor from any
source, including but not limited to: human glucocorticoid receptor
as disclosed in Weinberger, et al. Science 228, p 640-742 (1985),
and in Weinberger, et al. Nature, 318, p 670-672 (1986); rat
glucocorticoid receptor as disclosed in Miesfeld, R. Nature, 312, p
779-781 (1985); mouse glucocortoid receptor as disclosed in
Danielson, M. et al. EMBO J., 5, 2513; sheep glucocorticoid
receptor as disclosed in Yang, K., et al. J. Mol. Endocrinol. 8, p
173-180 (1992); marmoset glucocortoid receptor as disclosed in
Brandon, D. D., et al, J. Mol. Endocrinol. 7, p 89-96 (1991); and
human GR-beta as disclosed in Hollenberg, S M. et al. Nature, 318,
p 635, 1985, Bamberger, C. M. et al. J. Clin Invest. 95, p 2435
(1995).
[0117] The term, "disease or disorder associated with AP-1 and/or
NF-.kappa.B" as used herein, refers to a disease associated with
the expression product of a gene under the regulatory control of
AP-1 and/or NF-.kappa.B. Such diseases include, but are not limited
to: inflammatory and immune diseases and disorders; cancer and
tumor disorders, such as solid tumors, lymphomas and leukemia; and
fungal infections such as mycosis fungoides.
[0118] The term "inflammatory or immune associated diseases or
disorders" is used herein to encompass any condition, disease, or
disorder that has an inflammatory or immune component, including,
but not limited to, each of the following conditions: transplant
rejection (e.g., kidney, liver, heart, lung, pancreas (e.g., islet
cells), bone marrow, cornea, small bowel, skin allografts, skin
homografts (such as employed in burn treatment), heart valve
xenografts, serum sickness, and graft vs. host disease, autoimmune
diseases, such as rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, Type I and Type II diabetes, juvenile diabetes,
obesity, asthma, inflammatory bowel disease (such as Crohn's
disease and ulcerative colitis), pyoderma gangrenum, lupus
(systemic lupus erythematosis), myasthenia gravis, psoriasis,
dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary
inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's
thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome
(dry eyes/mouth), pernicious or immunohaemolytic anaemia,
atherosclerosis, Addison's disease (autoimmune disease of the
adrenal glands), idiopathic adrenal insufficiency, autoimmune
polyglandular disease (also known as autoimmune polyglandular
syndrome), glomerulonephritis, scleroderma, morphea, lichen planus,
viteligo (depigmentation of the skin), alopecia greata, autoimmune
alopecia, autoimmune hypopituatarism, Guillain-Barre syndrome, and
alveolitis; T-cell mediated hypersensitivity diseases, including
contact hypersensitivity, delayed-type hypersensitivity, contact
dermatitis (including that due to poison ivy), uticaria, skin
allergies, respiratory allergies (hayfever, allergic rhinitis) and
gluten-sensitive enteropathy (Celiac disease); inflammatory
diseases such as osteoarthritis, acute pancreatitis, chronic
pancreatitis, acute respiratory distress syndrome, Sezary's
syndrome and vascular diseases which have an inflammatory and or a
proliferatory component such as restenosis, stenosis and
artherosclerosis. Inflammatory or immune associated diseases or
disorders also includes, but is not limited to: endocrine
disorders, rheumatic disorders, collagen diseases, dermatologic
disease, allergic disease, ophthalmic disease, respiratory disease,
hematologic disease, gastrointestinal disease, inflammatory
disease, autoimmune disease, congenital adrenal hyperplasia,
nonsuppurative thyroiditis, hypercalcemia associated with cancer,
juvenile rheumatoid arthritis, Ankylosing spondylitis, acute and
subacute bursitis, acute nonspecific tenosynovitis, acute gouty
arthritis, post-traumatic osteoarthritis, synovitis of
osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus,
bullous dermatitis herpetiformis, severe erythema multiforme,
exfoliative dermatitis, seborrheic dermatitis, seasonal or
perennial allergic rhinitis, bronchial asthma, contact dermatitis,
atopic dermatitis, drug hypersensitivity reactions, allergic
conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and
iridocyclitis, chorioretinitis, optic neuritis, symptomatic
sarcoidosis, fulminating or disseminated pulmonary tuberculosis
chemotherapy, idiopathic thrombocytopenic purpura in adults,
secondary thrombocytopenia in adults, acquired (autoimmune)
hemolytic anemia, leukemias and lymphomas in adults, acute leukemia
of childhood, regional enteritis, autoimmune vasculitis, multiple
sclerosis, chronic obstructive pulmonary disease, solid organ
transplant rejection, sepsis. Preferred treatments include
treatment of transplant rejection, rheumatoid arthritis, psoriatic
arthritis, multiple sclerosis, Type 1 diabetes, asthma,
inflammatory bowel disease, systemic lupus erythematosis, psoriasis
and chronic pulmonary disease. In a particular embodiment, the
disease or disorder may be selected from transplant rejection,
rheumatoid arthritis, psoriatic arthritis multiple sclerosis, Type
I diabetes, asthma, inflammatory bowel disease, systemic lupus
erthematosis, psoriasis and chronic pulmony disease.
[0119] In addition, in accordance with the present invention a
method of treating a disease associated with AP-1-induced and/or
NF-.kappa.B-induced transcription (particularly AP-1-induced
transcription) is provided wherein a compound of formula (I) of the
invention is administered to a patient at risk of developing the
disease in a therapeutically effective amount to induce NHR
transrepression of the AP-1-induced and/or NF-.kappa.B-induced
transcription (particularly AP-1-induced transcription), thereby
treating the disease.
[0120] Other therapeutic agents, such as those described hereafter,
may be employed with the compounds of the invention in the present
methods. In the methods of the present invention, such other
therapeutic agent(s) may be administered prior to, simultaneously
with or following the administration of the compound(s) of the
present invention.
[0121] An embodiment of the present invention is a pharmaceutical
combination comprising compounds of Formula (I) and an
immunosuppressant, an anticancer agent, an anti-viral agent, an
anti-inflammatory agent, an anti-fungal agent, an anti-biotic, an
anti-vascular hyperproliferation agent, an anti-depressant agent, a
lipid-lowering agent, a lipid modulating agent, an antidiabetic
agent, an anti-obesity agent, an antihypertensive agent, a platelet
aggregation inhibitor, and/or an antiosteoporosis agent, wherein
the antidiabetic agent is 1, 2, 3 or more of a biguanide, a
sulfonyl urea, a glucosidase inhibitor, a PPAR .gamma. agonist, a
PPAR .alpha./.gamma. dual agonist, an SGLT2 inhibitor, a DP4
inhibitor, an aP2 inhibitor, an insulin sensitizer, a glucagon-like
peptide-1 (GLP-1), insulin and/or a meglitinide, wherein the
anti-obesity agent is a beta 3 adrenergic agonist, a lipase
inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid
receptor agonist, an aP2 inhibitor and/or an anorectic agent,
wherein the lipid lowering agent is an MTP inhibitor, an HMG CoA
reductase inhibitor, a squalene synthetase inhibitor, a fibric acid
derivative, an upregulator of LDL receptor activity, a lipoxygenase
inhibitor, or an ACAT inhibitor, wherein the antihypertensive agent
is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACE
inhibitor, calcium channel blocker and/or .beta.-adrenergic
blocker.
[0122] The antidiabetic agent may be 1, 2, 3 or more of metformin,
glyburide, glimepiride, glipyride, glipizide, chlorpropamide,
gliclazide, acarbose, miglitol, pioglitazone, troglitazone,
rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344,
L895645, YM-440, R-119702, AJ9677, repaglinde, nateglinide,
KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, P32/98
and/or NVP-DPP-728A, and the anti-obesity agent may be orlistat,
ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate,
axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or
mazindol, and the lipid_lowering agent may be pravastatin,
lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,
itavastatin, visastatin, fenofibrate, gemfibrozil, clofibrate,
avasimibe, TS-962, MD-700, cholestagel, niacin and/or LY295427, and
the antihypertensive agent may be an ACE inhibitor which is
captopril, fosinopril, enalapril, lisinopril, quinapril,
benazepril, fentiapril, ramipril or moexipril; and an NEP/ACE
inhibitor which may be omapatrilat,
[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dime-
thyl-7-oxo-1H-azepine-1-acetic acid (gemopatrilat) or CGS 30440;
and an angiotensin II receptor antagonist which may be irbesartan,
losartan or valsartan; amlodipine besylate, prazosin HCl,
verapamil, nifedipine, nadolol, propranolol, carvedilol, or
clonidine HCl, and the platelet aggregation inhibitor may be
aspirin, clopidogrel, ticlopidine, dipyridamole or ifetroban; and
the immunosuppressant may be a cyclosporin, mycophenolate,
interferon-beta, deoxyspergolin, FK-506 or Ant.-IL-2; and the
anti-cancer agent may be azathiprine, 5-fluorouracel,
cyclophosphamide, cisplatin, methotrexate, thiotepa, or
carboplatin; and the anti-viral agent may be abacavir, aciclovir,
ganciclovir, zidanocin, or vidarabine; and the antiinflammatory
drug may be ibuprofen, celecoxib, rofecoxib, aspirin, naproxen,
ketoprofen, diclofenac sodium, indomethacin, piroxicam, prednisone,
dexamethasone, hydrocortisone, or triamcinolone diacetate.
[0123] In a particular embodiment, the compounds of the present
invention are useful for the treatment of the aforementioned
exemplary disorders irrespective of their etiology, for example,
for the treatment of transplant rejection, rheumatoid arthritis,
inflammatory bowel disease, and viral infections.
Methods of Synthesis
[0124] The compounds of the present invention may be synthesized by
many methods available to those skilled in the art of organic
chemistry. General synthetic schemes, in accordance with the
present invention, for preparing compounds of the present invention
are described below. These schemes are illustrative and are not
meant to limit the possible techniques one skilled in the art may
use to prepare the compounds disclosed herein. Different methods to
prepare the compounds of the present invention will be evident to
those skilled in the art. Additionally, the various steps in the
synthesis may be performed in an alternate sequence in order to
give the desired compound or compounds. Examples of compounds of
the present invention prepared by methods described in the general
schemes are given in the preparations and examples section set out
hereinafter.
[0125] Scheme 1 outlines a general synthesis for a series of
4,5-dihydroindazoles. Many of the starting .beta.-keto esters 1 are
commercially available. Others are prepared following well known
literature procedures, such as reaction of acid chlorides
(R.sub.11b--COCl) with potassium methyl malonate (Clay et al.
Synthesis 1993, 290).
[0126] The alkylation of 1 may be effected with mild bases such as
potassium carbonate. A wide variety of alkylating reagents
(R.sub.11a-LG) may be used for this reaction. The leaving group
(LG) may be a halogen or sulfonate. After condensation of malonates
2 with (S)-alpha-methylbenzylamine, the stereoselective Michael
reaction of enamine intermediates 3 with methyl vinyl ketone may be
achieved under conditions reported by Nour et al. (Nour et al
Tetrahedron Asymmetry 2001, 12, 765). After hydrolysis of the
chiral amine auxiliary, diketones 4 can be obtained in
enantiomerically enriched form. The antipodes of 4 may be
synthesized from 2 using the other .alpha.-methylbenzylamine
enantiomer. Alternative syntheses of diketones 4 include
enantioselective Michael reaction to methyl vinyl ketone with a
palladium catalyst (Hamashima et al. J. Am. Chem. Soc. 2002, 124,
11240), La-Na-BINOL complex (Sasai et al Tetrahedron Lett. 1996,
37, 5561), and copper catalyst (Christoffers et al Chem. Eur. J.
2001, 7, 1014). Diketones 4 can also be synthesized in racemic form
from 2 and methyl vinyl ketone in the presence of catalytic amount
of bases, such as sodium hydride (Begue et al Synth. Commun. 1992,
22, 573), or Lewis acids, such as ytterbium(III)
trifluoromethanesulfonate (Keller et al Tetrahedron Lett. 1996, 37,
1879). The resolution of 4 or subsequent intermediates may be
achieved using a variety of chiral HPLC columns.
[0127] Intramolecular aldol condensation of 4, in the presence of
piperidine and acetic acid gives Hagemann's esters 5, which, in
turn, can be converted to keto aldehydes 6 with ethyl formate,
sodium in ethanol and ether. Treatment of 6 with hydrazines
(R.sub.1--NHNH.sub.2), sodium acetate and acetic acid would yield
4,5-dihydroindazole intermediates 7, which may then be reduced to
aldehydes 8 with diisobutylaluminum hydride. Reaction of 8 with
organo lithium or magnesium reagents (R.sub.10--X-M) would give the
corresponding alcohols 10 (n=0). Alternatively, 8 may be elongated
to aldehydes 9 via reaction with
(methoxymethylene)triphenylphosphorane followed by acid hydrolysis.
Aldehydes 9 can react with R.sub.10--X-M to provide 10 (n=1).
Alcohols 10 may then be oxidzed to ketones 11 under oxidation
conditions, such as tetrapropylammonium perruthenate (TPAP) or
Dess-Martin periodinane. Tertiary alcohols 12 may be obtained from
11 using organolithium or magnesium reagents (R.sub.8-M). Analogues
of 12 where R.sub.8 is trifluoromethyl group may be prepared with
(trifluoromethyl)trimethylsilane and tetrabutylammonium fluoride.
Alcohols 10 can also be converted to variety of ethers (12a) with
alkylating reagents (R.sub.12-LG) under basic conditions such as
sodium hydride in N,N-dimethyl formamide. ##STR8##
[0128] Scheme 2 outlines a general synthesis for a series of
4,5,6,7-tetrahydroindazoles. Treatment of ethyl
4-oxocyclohexanecarboxylate (13) with sodium ethoxide and ethyl
formate would provide keto aldehydes 14, which can be converted to
4,5,6,7-tetrahydroindazoles 15 with hydrazines
(R.sub.1--NHNH.sub.2), sodium acetate and acetic acid.
Incorporation of R.sub.11a can be achieved by alkylation with LDA
and R.sub.11a-LG. Addition of hexamethylphosphoramide (HMPA) may
improve the efficiency of reaction. Subsequent transformations are
analogous to those described above for the 4,5-dihydroindazole
series. Various secondary alcohols (19), ketones (20), tertiary
alcohols (21) and ethers (19a) of the 4,5,6,7-tetrahydroindazoles
can be synthesized using this route. ##STR9##
[0129] Aldehydes 8 and 9 from Scheme 1 can be useful intermediates
for diversification. They can be reacted under Horner-Emmons or
Wittig conditions to yield olefins 22 (Scheme 3). They can be
reacted with amines (R.sub.10--NH.sub.2) under reductive conditions
such as sodium triacetoxyborohydride to give secondary amines 23,
which can be further derivatized to tertiary amines 24 under
similar conditions. Alternatively, they can be converted to primary
amines 25 by reaction with O-benzylhydroxylamine (NH.sub.2OBn) to
form oximes and reduction using conditions such as zinc in formic
acid at elevated temperature. These primary amines can be converted
to amides, carbamates and ureas (26) by reaction with acid
chlorides, chloroformates, carbamoyl chlorides and isocyanates.
Aldehydes 8 and 9 can also be converted to acetals 27 using
trimethylsilyl trifluoromethanesulfonate (TMSOTf) conditions
reported by Tsunoda et al (Tetrahedron Lett. 1980, 21, 1357).
Furthermore, aldehydes 8 and 9 can be reduced with sodium
borohydride, diisobutylaluminum hydride or lithium aluminum hydride
to give alcohols 28, another useful intermediate for
diversification. For example, 28 can react with acid chlorides,
chloroformates, carbamoyl chloride and isocyanates to yield esters,
carbonates and carbamates (29). 28 can also react with disulfide
(R.sub.10SSR.sub.10) under Mitsunobu conditions to give sulfides
30, which can be oxidized to sulfoxides and sulfones 31 using oxone
or metachloroperbenzoic acid. ##STR10##
[0130] A series of amide derivatives 35 can be prepared following a
sequence outlined in Scheme 4. Esters 7 can be converted to acids
32 using saponification conditions such as sodium hydroxide in
methanol and water (for methyl or ethyl esters) or acidic
conditions such as hydrogen chloride or trifluoroacetic acid (for
t-butyl esters). Oxidation of aldehydes 9 under Sharpless sodium
chlorite conditions will give acids 33. For preparation of acids
34, aldehydes 8 can be treated with stabilized Wittig ylide
(Ph.sub.3PCHCO.sub.2Me). The resulting enoates could be selectively
reduced with magnesium in methanol (Hudlicky et al. Tetrahedron
Lett. 1987, 28, 5287). Subsequent hydrolysis with lithium hydroxide
can provide the desired acids 34. Acids 32-34 can be coupled with
variety of amines under standard coupling conditions, such as EDC,
DCC, or BOP conditions, to give amides 35. ##STR11##
Definition of Terms
[0131] The following are definitions of terms used in this
specification and appended claims. The initial definition provided
for a group or term herein applies to that group or term throughout
the specification and claims, individually or as part of another
group, unless otherwise indicated.
[0132] The term "alkyl" refers to straight or branched chain
hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 6
carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4
carbon atoms, are most preferred. When numbers appear in a
subscript after the symbol "C", the subscript defines with more
specificity the number of carbon atoms that a particular group may
contain. For example, "C.sub.1-6alkyl" refers to straight and
branched chain alkyl groups with one to six carbon atoms, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and
so forth. The subscript "0" refers to a bond. Thus, the term
hydroxy(C.sub.0-2)alkyl or (C.sub.0-2)hydroxyalkyl includes
hydroxy, hydroxymethyl and hydroxyethyl.
[0133] The term "substituted alkyl" refers to an alkyl group as
defined above having one, two, or three substituents selected from
the group consisting of halo (e.g., trifluoromethyl), alkenyl,
substituted alkenyl, alkynyl, nitro, cyano, oxo (.dbd.O), OR.sub.a,
SR.sub.a, (.dbd.S), --NR.sub.aR.sub.b, --N(alkyl).sub.3.sup.+,
--NR.sub.aSO.sub.2, --NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.c
--SO.sub.2NR.sub.aR.sub.b, --SO.sub.2NR.sub.aC(.dbd.O)R.sub.b,
SO.sub.3H, --PO(OH).sub.2, --C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, .dbd.N--OH,
.dbd.N--O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,
wherein R.sub.a and R.sub.b are selected from hydrogen, alkyl,
alkenyl, CO.sub.2H, CO.sub.2(alkyl), C.sub.3-7cycloalkyl, phenyl,
benzyl, phenylethyl, napthyl, a four to seven membered heterocyclo,
or a five to six membered heteroaryl, or when attached to the same
nitrogen atom may join to form a heterocyclo or heteroaryl, and
R.sub.c is selected from same groups as R.sub.a and R.sub.b but is
not hydrogen. Each group R.sub.a and R.sub.b when other than
hydrogen, and each R.sub.c group optionally has up to three further
substituents attached at any available carbon or nitrogen atom of
R.sub.a, R.sub.b, and/or R.sub.c, said substituent(s) being
selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, hydroxy, halogen, cyano, nitro, CF.sub.3,
O(C.sub.1-6alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-6alkyl), CO.sub.2H, CO.sub.2(C.sub.1-6alkyl),
NHCO.sub.2(C.sub.1-6alkyl), --S(C.sub.1-6alkyl), --NH.sub.2,
NH(C.sub.1-6alkyl), N(C.sub.1-6alkyl).sub.2,
N(CH.sub.3).sub.3.sup.+, SO.sub.2(C.sub.1-6alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl),
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2,
C.sub.3-7cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy,
benzyloxy, napthyl, a four to seven membered heterocyclo, or a five
to six membered heteroaryl. When a substituted alkyl is substituted
with an aryl, heterocyclo, cycloalkyl, or heteroaryl group, said
ringed systems are as defined below and thus may have zero, one,
two, or three substituents, also as defined below.
[0134] One skilled in the field will understand that, when the
designation "CO.sub.2" is used herein, this is intended to refer to
the group ##STR12##
[0135] When the term "alkyl" is used together with another group,
such as in "arylalkyl", this conjunction defines with more
specificity at least one of the substituents that the substituted
alkyl will contain. For example, "arylalkyl" refers to a
substituted alkyl group as defined above where at least one of the
substituents is an aryl, such as benzyl. Thus, the term
aryl(C.sub.0-4)alkyl includes a substituted lower alkyl having at
least one aryl substituent and also includes an aryl directly
bonded to another group, i.e., aryl(C.sub.0)alkyl.
[0136] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
double bond. Alkenyl groups of 2 to 6 carbon atoms and having one
double bond are most preferred.
[0137] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one
triple bond are most preferred.
[0138] The term "alkylene" refers to bivalent straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1
to 6 carbon atoms, e.g., {--CH.sub.2--}.sub.n, wherein n is 1 to
12, preferably 1-6. Lower alkylene groups, that is, alkylene groups
of 1 to 4 carbon atoms, are most preferred. The terms "alkenylene"
and "alkynylene" refer to bivalent radicals of alkenyl and alkynyl
groups, respectively, as defined above.
[0139] When reference is made to a substituted alkenyl, alkynyl,
alkylene, alkenylene, or alkynylene group, these groups are
substituted with one to three substitutents as defined above for
substituted alkyl groups.
[0140] The term "heteroalkylene" is used herein to refer to
saturated and unsaturated bivalent straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 8
carbon atoms, wherein one or two carbon atoms in the straight chain
are replaced by heteroatom(s) selected from --O--, --S--,
--S(.dbd.O)--, --SO.sub.2--, --NH--, and --NHSO.sub.2--. Thus, the
term "heteroalkylene" includes bivalent alkoxy, thioalkyl, and
aminoalkyl groups, as defined below, as well as alkylene and
alkenylene groups having a combination of heteroatoms in the alkyl
chain. As an illustration, a "heteroalkylene" herein may comprise
groups such as --S--(CH.sub.2).sub.1-5NH--CH.sub.2--,
--O--(CH.sub.2).sub.1-5S(.dbd.O)--CH.sub.2--,
--NHSO.sub.2--CH.sub.2--, --CH.sub.2--NH--, and so forth.
Preferably, a heteroalkylene does not have two adjacent atoms
simultaneously selected from --O-- and --S--. When a subscript is
used with the term heteroalkylene, e.g., as in
|C.sub.2-3heteroalkylene, the subscript refers to the number of
carbon atoms in the group in addition to heteroatoms. Thus, for
example, a C.sub.1-2 heteroalkylene may include groups such as
--NH--CH.sub.2--, --CH.sub.2--NH--CH.sub.2--,
--CH.sub.2--CH.sub.2--NH--, --S--CH.sub.2--,
--CH.sub.2--S--CH.sub.2--, --O--CH.sub.2--NH--CH.sub.2--,
CH.sub.2--O--CH.sub.2 and so forth.
[0141] The term "substituted heteroalkylene" refers to a
heteroalkylene group as defined above wherein at least one of the
nitrogen or carbon atoms in the heteroalkylene chain is bonded to
(or substituted with) a group other than hydrogen. Carbon atoms in
the heteroalkylene chain may be substituted with a group selected
from those recited above for substituted alkyl groups, or with a
further alkyl or substituted alkyl group. Nitrogen atoms of the
heteroalkylene chain may be substituted with a group selected from
alkyl, alkenyl, alkynyl, cyano, or A.sub.1-Q-A.sub.2-R.sub.h,
wherein A.sub.1 is a bond, C.sub.1-2alkylene, or
C.sub.2-3alkenylene; Q is a bond, --C(.dbd.O)--,
--C(.dbd.O)NR.sub.d--, --C(.dbd.S)NR.sub.d--, --SO.sub.2--,
--SO.sub.2NR.sub.d--, --CO.sub.2--, or --NR.sub.dCO.sub.2--;
A.sub.2 is a bond, C.sub.1-3alkylene, C.sub.2-3alkenylene,
--C.sub.1-4alkylene-NR.sub.d--,
--C.sub.1-4alkylene-NR.sub.dC(.dbd.O)--, --C.sub.1-4alkylene-S--,
--C.sub.1-4alkylene-SO.sub.2--, or --C.sub.1-4alkylene-O--, wherein
said A.sub.2 alkylene groups are branched or straight chain and
optionally substituted as defined herein for substituted alkylene;
R.sub.h is hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclo, or cycloalkyl; and R.sub.d
is selected from hydrogen, alkyl, and substituted alkyl, as defined
herein, provided, however, that for a substituted heteralkylene
R.sub.h is not hydrogen when A.sub.1, Q and A.sub.2 are each bonds.
When R.sub.h is aryl, heteroaryl, cycloalkyl, or heterocyclo, these
rings are, in turn, optionally substituted with one to three groups
as defined below in the definitions for these terms.
[0142] The term "alkoxy" refers to an alkyl or substituted alkyl
group as defined above having one or two oxygen atoms (--O--) in
the alkyl chain. For example, the term "alkoxy" includes the groups
--O--C.sub.1-2alkyl, --C.sub.1-6alkylene)-O--C.sub.1-6alkyl,
--C.sub.1-4alkylene-O--C.sub.1-4alkylene)-O--C.sub.1-4alkyl, and so
forth.
[0143] The term "thioalkyl" or "alkylthio" refers to an alkyl or
substituted alkyl group as defined having one or two sulfur atoms
in the alkyl chain. For example, the term "thioalkyl" or
"alkylthio" includes the groups --S--C.sub.1-12alkyl,
--(S--C.sub.1-6alkylene)-S--C.sub.1-6alkyl, and so forth.
[0144] The terms "aminoalkyl" or "alkylamino" refer to an alkyl or
substituted alkyl group as defined above having one or two nitrogen
(--NR--) atoms in the alkyl chain. For example, the term
"aminoalkyl" includes the groups --NR--C.sub.1-12alkyl,
--NR--C.sub.1-6alkylene-NR--C.sub.1-6alkyl, etc. (where R is
preferably hydrogen but may include alkyl or substituted alkyl as
defined above.) When a subscript is used with reference to an
alkoxy, thioalkyl or aminoalkyl, the subscript refers to the number
of carbon atoms that the group may contain in addition to
heteroatoms. Thus, for example, monovalent C.sub.1-2aminoalkyl
includes the groups --CH.sub.2--NH.sub.2, --NH--CH.sub.3,
--(CH.sub.2).sub.2--NH.sub.2, --NH--CH.sub.2--CH.sub.3,
--CH.sub.2--NH.sub.2--CH.sub.3, and --N--(CH.sub.3).sub.2. A lower
aminoalkyl comprises an aminoalkyl having one to four carbon atoms.
"Amino" refers to the group NH.sub.2. The alkoxy, thioalkyl, or
aminoalkyl groups may be monovalent or bivalent. By "monovalent" it
is meant that the group has a valency (i.e., ability to combine
with another group), of one, and by "bivalent" it is meant that the
group has a valency of two. Thus, for example, a monovalent alkoxy
includes groups such as --O--C.sub.1-12alkyl,
--C.sub.1-6alkylene-O--C.sub.1-6alkyl,
--C.sub.4alkylene-O--C.sub.1-4alkylene-O--C.sub.1-4alkyl, whereas a
bivalent alkoxy includes groups such as --O--C.sub.1-12alkylene-,
--C.sub.1-6alkylene-O--C.sub.1-6alkylene-,
--C.sub.1-4alkylene-O--C.sub.1-4alkylene-O--C.sub.1-4alkylene-, and
so forth. Where a bivalent group is specified, attachment may occur
at either end of the bivalent group. For example bivalent groups
such as --Oalkylene-, --N(R.sub.14)--C(O)--,
--N(R.sub.14)--C(O)O--, and --NR.sub.15C(O)NR.sub.16.sup.-, are
also intended to include -alkyleneO--, --C(O)--N(R.sub.14)--,
--OC(O)N(R.sub.14)--, and --NR.sub.16C(O)NR.sub.15--. Accordingly a
compound having an asymmetric bivalent group indicates two
compounds having differing attachment.
[0145] It should be understood that the selections for alkoxy,
thioalkyl, and aminoalkyl will be made by one skilled in the field
to provide stable compounds. Thus, for example, in compounds of
formula (I), when G is attached to a nitrogen atom (N*) of ring A
and is selected from an alkoxy or alkylthio group, the alkoxy and
alkylthio groups will have at least one carbon atom bonded directly
to ring A (at N*), with the oxygen or sulfur atoms being at least
one atom away from said nitrogen atom.
[0146] The term "acyl" refers to a carbonyl group linked to an
organic radical, more particularly, the group C(.dbd.O)R.sub.e, as
well as the bivalent groups --C(.dbd.O)-- or --C(.dbd.O)R.sub.e--,
which are linked to organic radicals or ring A in compounds of
formula (I). The group R.sub.e can be selected from alkyl, alkenyl,
alkynyl, aminoalkyl, substituted alkyl, substituted alkenyl, or
substituted alkynyl, as defined herein, or when appropriate, the
corresponding bivalent group, e.g., alkylene, alkenylene, etc.
Accordingly, in compounds of formula (I), the groups
--C(.dbd.O)R.sub.e-- or --R.sub.eC(.dbd.O)--, wherein in this
instance, the group R.sub.e will be selected from bivalent groups,
e.g., alkylene, alkenylene, alkynylene, bivalent aminoalkyl,
substituted alkylene, substituted alkenylene, or substituted
alkynylene.
[0147] The term "alkoxycarbonyl" refers to a carboxy group
##STR13## linked to an organic radical (CO.sub.2R.sub.e), as well
as the bivalent groups --CO.sub.2--, --CO.sub.2R.sub.e-- which are
linked to organic radicals in compounds of formula (I), wherein
R.sub.e is as defined above for acyl. The organic radical to which
the carboxy group is attached may be monovalent (e.g.,
--CO.sub.2-alkyl or --OC(.dbd.O)alkyl), or bivalent (e.g.,
--CO.sub.2-alkylene, --OC(.dbd.O)alkylene, etc.) Accordingly, in
compounds of formula (I), when it is recited that G can be
"alkoxycarbonyl," this is intended to encompass a selection for G
of --CO.sub.2-- and also the groups --CO.sub.2R.sub.e-- or
--R.sub.eCO.sub.2--, wherein in this instance, the group R.sub.e
will be selected from bivalent groups, e.g., alkylene, alkenylene,
alkynylene, bivalent aminoalkyl, substituted alkylene, substituted
alkenylene, or substituted alkynylene.
[0148] The term "amide" or "amidyl" refers to the group
C(.dbd.O)NR.sub.aR.sub.b, wherein the groups R.sub.a and R.sub.b
are defined as recited above in the definition for substituted
alkyl groups.
[0149] The term "sulfonyl" refers to a sulphoxide group linked to
an organic radical in compounds of formula (I), more particularly,
the monovalent group S(O).sub.1-2--R.sub.e, or the bivalent group
--S(O).sub.1-2-- linked to organic radicals in compounds of formula
(I). Accordingly, in compounds of formula (I), when it is recited
that G can be "sulfonyl," this is intended to encompass a selection
for G of --S(.dbd.O)-- or --SO.sub.2-- as well as the groups
--S(.dbd.O)R.sub.e--, --R.sub.eS(.dbd.O)--, --SO.sub.2R.sub.e--, or
--R.sub.eSO.sub.2--, wherein in this instance, the group R.sub.e
will be selected from those recited above for acyl and
alkoxycarbonyl groups.
[0150] The term "sulfonamidyl" refers to the group
--S(O).sub.2NR.sub.aR.sub.b, wherein R.sub.a and R.sub.b are as
defined above for substituted alkyl groups. Additionally, the
sulfonamidyl group may be bivalent, in which case one of the groups
R.sub.a and R.sub.b will be a bond. Thus, in compounds of formula
(I), when it is stated that G may be sulfonamidyl, it is intended
to mean that G is a group --S(O).sub.2NR.sub.a--.
[0151] The term "cycloalkyl" refers to fully saturated and
partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to
7 carbon atoms. The term "cycloalkyl" includes such rings having
zero, one, two, or three substituents selected from the group
consisting of halogen, trifluoromethyl, trifluoromethoxy, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro,
cyano, oxo (.dbd.O), OR.sub.a, SR.sub.a, (.dbd.S),
--NR.sub.aR.sub.b, --N(alkyl).sub.3+, --NR.sub.aSO.sub.2,
--NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.e
--SO.sub.2NR.sub.aR.sub.b, --SO.sub.2NR.sub.aC(.dbd.O)R.sub.b,
SO.sub.3H, --PO(OH).sub.2, --C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, .dbd.N--OH,
.dbd.N--O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,
wherein R.sub.a, R.sub.b and R.sub.e are as defined above for
substituted alkyl groups, and are also in turn optionally
substituted as recited above in the definition for substituted
alkyl groups. The term "cycloalkyl" also includes such rings having
a second ring fused thereto (e.g., including benzo, heterocyclo, or
heteroaryl rings) or having a carbon-carbon bridge of 3 to 4 carbon
atoms. When a cycloalkyl is substituted with a further ring (or has
a second ring fused thereto), said ring in turn is optionally
substituted with one to two of (C.sub.1-4)alkyl,
(C.sub.2-4)alkenyl, halogen, hydroxy, cyano, nitro, CF.sub.3,
O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl), and/or
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2.
[0152] Accordingly, in compounds of formula (I), the term
"cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,
etc., as well as the following ring systems, ##STR14## and the
like, which optionally may be substituted at any available atoms of
the ring(s). Preferred cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, ##STR15##
[0153] The term "halo" or "halogen" refers to chloro, bromo, fluoro
and iodo.
[0154] The term "haloalkyl" means a substituted alkyl having one or
more halo substituents. For example, "haloalkyl" includes mono, bi,
and trifluoromethyl.
[0155] The term "haloalkoxy" means an alkoxy group having one or
more halo substituents. For example, "haloalkoxy" includes
OCF.sub.3.
[0156] The term "aryl" refers to phenyl, biphenyl, 1-naphthyl and
2-naphthyl. The term "aryl" includes such rings having zero, one,
two or three substituents selected from the group consisting of
halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano,
OR.sub.a, SR.sub.a, (.dbd.S), --NR.sub.aR.sub.b,
--N(alkyl).sub.3.sup.+, --NR.sub.aSO.sub.2,
--NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.c
--SO.sub.2NR.sub.aR.sub.b, --SO.sub.2NR.sub.aC(.dbd.O)R.sub.b,
SO.sub.3H, --PO(OH).sub.2, --C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, aryl, cycloalkyl,
heterocyclo, and/or heteroaryl, wherein R.sub.a, R.sub.b and
R.sub.c are as defined above for substituted alkyl groups, and are
also in turn optionally substituted as recited above. Additionally,
two substituents attached to an aryl, particularly a phenyl group,
may join to form a further ring such as a fused or spiro-ring,
e.g., cyclopentyl or cyclohexyl, or fused heterocyclo or
heteroaryl. When an aryl is substituted with a further ring (or has
a second ring fused thereto), said ring in turn is optionally
substituted with one to two of (C.sub.1-4)alkyl,
(C.sub.2-4)alkenyl, halogen, hydroxy, cyano, nitro, CF.sub.3,
O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl), and/or
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2.
[0157] Thus, examples of aryl groups include: ##STR16## and the
like, which optionally may be substituted at any available carbon
or nitrogen atom. A preferred aryl group is optionally-substituted
phenyl.
[0158] The terms "heterocyclo" or "heterocyclic" refers to
substituted and unsubstituted non-aromatic 3 to 7 membered
monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15
membered tricyclic groups, in which at least one of the rings has
at least one heteroatom (O, S or N). Each ring of the heterocyclo
group containing a heteroatom can contain one or two oxygen or
sulfur atoms and/or from one to four nitrogen atoms provided that
the total number of heteroatoms in each ring is four or less, and
further provided that the ring contains at least one carbon atom.
The fused rings completing bicyclic and tricyclic groups may
contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen atoms may optionally be
quaternized. The heterocyclo group may be attached at any available
nitrogen or carbon atom. The heterocyclo ring may contain zero,
one, two or three substituents selected from the group consisting
of halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano, oxo
(.dbd.O), OR.sub.a, SR.sub.a, (.dbd.S), NR.sub.aR.sub.b,
--N(alkyl).sub.3.sup.+, --NR.sub.aSO.sub.2,
NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.c
--SO.sub.2NR.sub.aR.sub.b, --SO.sub.2NR.sub.aC(.dbd.O)R.sub.b,
SO.sub.3H, --PO(OH).sub.2, --C(.dbd.O)R.sub.a, CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, --N--OH,
.dbd.N--O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,
wherein R.sub.a, R.sub.b and R.sub.c are as defined above for
substituted alkyl groups, and are also in turn optionally
substituted as recited above. When a heterocyclo is substituted
with a further ring, said ring in turn is optionally substituted
with one to two of (C.sub.1-4)alkyl, (C.sub.2-4)alkenyl, halogen,
hydroxy, cyano, nitro, CF.sub.3, O(C.sub.1-4alkyl), OCF.sub.3,
C(.dbd.O)H, C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), NHCO.sub.2(C.sub.1-4alkyl),
--S(C.sub.1-4alkyl), --NH.sub.2, NH(C.sub.1-4alkyl),
N(C.sub.4alkyl).sub.2, N(C.sub.1-4alkyl).sub.3.sup.+,
SO.sub.2(C.sub.1-4alkyl), C(.dbd.O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl), and/or
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2.
[0159] Exemplary monocyclic groups include azetidinyl,
pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic
heterocyclo groups include quinuclidinyl.
[0160] Preferred heterocyclo groups in compounds of formula (I)
include ##STR17## which optionally may be substituted.
[0161] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10
membered bicyclic groups, and 11 to 14 membered tricyclic groups
which have at least one heteroatom (O, S or N) in at least one of
the rings. Each ring of the heteroaryl group containing a
heteroatom can contain one or two oxygen or sulfur atoms and/or
from one to four nitrogen atoms provided that the total number of
heteroatoms in each ring is four or less and each ring has at least
one carbon atom. The fused rings completing the bicyclic and
tricyclic groups may contain only carbon atoms and may be
saturated, partially saturated, or unsaturated. The nitrogen and
sulfur atoms may optionally be oxidized and the nitrogen atoms may
optionally be quaternized. Heteroaryl groups which are bicyclic or
tricyclic must include at least one fully aromatic ring but the
other fused ring or rings may be aromatic or non-aromatic. The
heteroaryl group may be attached at any available nitrogen or
carbon atom of any ring. The heteroaryl ring system may contain
zero, one, two or three substituents selected from the group
consisting of halogen, trifluoromethyl, trifluoromethoxy, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro,
cyano, OR.sub.a, SR.sub.a, (.dbd.S), --NR.sub.aR.sub.b,
--N(alkyl).sub.3.sup.+, --NR.sub.aSO.sub.2,
--NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.c
--SO.sub.2NR.sub.aR.sub.b, --SO.sub.2NR.sub.aC(.dbd.O)R.sub.b,
SO.sub.3H, --PO(OH).sub.2, C(.dbd.O)R.sub.a, --CO.sub.2R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b,
--C(.dbd.O)(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--C(.dbd.O)NR.sub.a(SO.sub.2)R.sub.b,
--CO.sub.2(C.sub.1-4alkylene)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, NR.sub.aCO.sub.2R.sub.b,
--NR.sub.a(C.sub.1-4alkylene)CO.sub.2R.sub.b, aryl, cycloalkyl,
heterocyclo, and/or heteroaryl, wherein R.sub.a, R.sub.b and
R.sub.c are as defined above for substituted alkyl groups, and are
also in turn optionally substituted as recited above. When a
heteroaryl is substituted with a further ring, said ring in turn is
optionally substituted with one to two of (C.sub.1-4)alkyl,
(C.sub.2-4)alkenyl, halogen, hydroxy, cyano, nitro, CF.sub.3,
O(C.sub.1-4alkyl), OCF.sub.3, C(.dbd.O)H,
C(.dbd.O)(C.sub.1-4alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4alkyl),
NHCO.sub.2(C.sub.1-4alkyl), --S(C.sub.1-4alkyl), --NH.sub.2,
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
N(C.sub.1-4alkyl).sub.3.sup.+, SO.sub.2(C.sub.1-4alkyl),
C(--O)(C.sub.1-4alkylene)NH.sub.2,
C(.dbd.O)(C.sub.1-4alkylene)NH(alkyl), and/or
C(.dbd.O)(C.sub.1-4alkylene)N(C.sub.1-4alkyl).sub.2.
[0162] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl and the like.
[0163] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the
like.
[0164] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0165] In compounds of formula (I), preferred heteroaryl groups
include ##STR18## and the like, which optionally may be substituted
at any available carbon or nitrogen atom.
[0166] CAS Registry Number refers to the unique identifier number
assigned to chemical compounds by the Chemical Abstracts Service, a
division of the American Chemical Society.
[0167] Unless otherwise indicated, when reference is made to a
specifically-named aryl (e.g., phenyl), cycloalkyl (e.g.,
cyclohexyl), heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g.,
imidazolyl), unless otherwise specifically indicated the reference
is intended to include rings having 0 to 3, preferably 0-2,
substituents selected from those recited above for the aryl,
cycloalkyl, heterocyclo and/or heteroaryl groups, as
appropriate.
[0168] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0169] The term "carbocyclic" means a saturated or unsaturated
monocyclic or bicyclic ring in which all atoms of all rings are
carbon. Thus, the term includes cycloalkyl and aryl rings. The
carbocyclic ring may be substituted in which case the substituents
are selected from those recited above for cycloalkyl and aryl
groups.
[0170] The term "optionally substituted" is intended to include
both unsubstituted and substituted groups.
[0171] When the term "unsaturated" is used herein to refer to a
ring or group, the ring or group may be fully unsaturated or
partially unsaturated.
[0172] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds and compounds useful as
pharmaceutically-acceptable compounds and/or intermediate compounds
useful in making pharmaceutically-acceptable compounds.
[0173] The term "prodrug" denotes a compound which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of the formula
(I), and/or a salt and/or solvate thereof. For example, compounds
containing a carboxy group can form physiologically hydrolyzable
esters which serve as prodrugs by being hydrolyzed in the body to
yield formula (I) compounds per se. Such prodrugs are preferably
administered orally since hydrolysis in many instances occurs
principally under the influence of the digestive enzymes.
Parenteral administration may be used where the ester per se is
active, or in those instances where hydrolysis occurs in the blood.
Examples of physiologically hydrolyzable esters of compounds of
formula (I) include C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl,
phthalyl, methoxymethyl, C.sub.1-6alkanoyloxy-C.sub.1-6alkyl, e.g.
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl,
C.sub.1-6alkoxycarbonyloxy-C.sub.1-6alkyl, e.g.
methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well known
physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
conventional techniques known in the art.
[0174] Prodrug ester examples include the following groups:
(1-alkanoyloxy)alkyl such as, ##STR19## wherein R.sup.z, R.sup.t
and R.sup.y are H, alkyl, aryl or arylalkyl; however, R.sup.zO
cannot be HO.
[0175] Examples of such prodrug esters include ##STR20##
[0176] Other examples of suitable prodrug esters include ##STR21##
wherein R.sub.z can be H, alkyl (such as methyl or t-butyl),
arylalkyl (such as benzyl) or aryl (such as phenyl); R.sup.v is H,
alkyl, halogen or alkoxy, R.sup.u is alkyl, aryl, arylalkyl or
alkoxyl, and n.sub.1 is 0, 1 or 2.
[0177] For further examples of prodrug derivatives, see:
[0178] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985) and Methods in Enzymology, Vol. 112, pp. 309-396, edited by
K. Widder, et al. (Academic Press, 1985);
[0179] b) A Textbook of Drug Design and Development, edited by
Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and
Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991);
and
[0180] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, pp. 1-38
(1992).
[0181] The term tautomer refers to compounds of the formula (I) and
salts thereof that may exist in their tautomeric form, in which
hydrogen atoms are transposed to other parts of the molecules and
the chemical bonds between the atoms of the molecules are
consequently rearranged. It should be understood that the all
tautomeric forms, insofar as they may exist, are included within
the invention.
[0182] The terms pharmaceutically acceptable "salt" and "salts"
refer to basic salts formed with inorganic and organic bases. Such
salts include ammonium salts; alkali metal salts, such as lithium,
sodium and potassium salts (which are preferred); alkaline earth
metal salts, such as calcium and magnesium salts; salts with
organic bases, such as amine like salts (e.g., dicyclohexylamine
salt, benzathine, N-methyl-D-glucamine, and hydrabamine salts); and
salts with amino acids like arginine, lysine and the like; and
zwitterions, the so-called "inner salts". Nontoxic,
pharmaceutically acceptable salts are preferred, although other
salts are also useful, e.g., in isolating or purifying the
product.
[0183] The term pharmaceutically acceptable "salt" and "salts" also
includes acid addition salts. These are formed, for example, with
strong inorganic acids, such as mineral acids, for example sulfuric
acid, phosphoric acid or a hydrohalic acid such as HCl or HBr, with
strong organic carboxylic acids, such as alkanecarboxylic acids of
1 to 4 carbon atoms which are unsubstituted or substituted, for
example, by halogen, for example acetic acid, such as saturated or
unsaturated dicarboxylic acids, for example oxalic, malonic,
succinic, maleic, fumaric, phthalic or terephthalic acid, such as
hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,
malic, tartaric or citric acid, such as amino acids, (for example
aspartic or glutamic acid or lysine or arginine), or benzoic acid,
or with organic sulfonic acids, such as (C.sub.1-C.sub.4) alkyl or
arylsulfonic acids which are unsubstituted or substituted, for
example by halogen, for example methanesulfonic acid or
p-toluenesulfonic acid.
[0184] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The compounds of the present invention can have
asymmetric centers at any of the carbon atoms including any one or
the R substituents. Consequently, compounds of formula I can exist
in enantiomeric or diastereomeric forms or in mixtures thereof. The
processes for preparation can utilize racemates, enantiomers or
diastereomers as starting materials. When diastereomeric or
enantiomeric products are prepared, they can be separated by
conventional methods for example, chromatographic or fractional
crystallization.
[0185] The inventive compounds may be in the free or solvate (e.g.
hydrate) form.
Combinations
[0186] Where desired, the compounds of structure I may be used in
combination with one or more other types of therapeutic agents such
as immunosuppressants, anticancer agents, anti-viral agents,
anti-inflammatory agents, anti-fungal agents, antibiotics,
anti-vascular hyperproliferation agents, anti-depressive agents,
hypolipidemic agents or lipid-lowering agents or lipid modulating
agents, antidiabetic agents, anti-obesity agents, antihypertensive
agents, platelet aggregation inhibitors, and/or anti-osteoporosis
agents, which may be administered orally in the same dosage form,
in a separate oral dosage form or by injection.
[0187] The immunosuppressants which may be optionally employed in
combination with compounds of formula I of the invention include
cyclosporins, for example cyclosporin A, mycophenolate,
interferon-beta, deoxyspergolin, FK-506 or Ant.-IL-2.
[0188] The anti-cancer agents which may be optionally employed in
combination with compounds of formula I of the invention include
azathiprine, 5-fluorouracil, cyclophosphamide, cisplatin,
methotrexate, thiotepa, carboplatin, and the like.
[0189] The anti-viral agents which may be optionally employed in
combination with compounds of formula I of the invention include
abacavir, aciclovir, ganciclovir, zidanocin, vidarabine, and the
like.
[0190] The anti-inflammatory agents which may be optionally
employed in combination with compounds of formula I of the
invention include non-steroidal anti-inflammatory drugs (NSAIDs)
such as ibuprofen, cox-2 inhibitors such as celecoxib, rofecoxib,
aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin,
piroxicam, steroids such as prednisone, dexamethasone,
hydrocortisone, triamcinolone diacetate, gold compounds, such as
gold sodium thiomalate, TNF-.alpha. inhibitors such as tenidap,
anti-TNF antibodies or soluble TNF receptor, and rapamycin
(sirolimus or Rapamune) or derivatives thereof, infliximab
(Remicade.RTM. Centocor, Inc.). CTLA-4Ig, LEA29Y, antibodies such
as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB,
anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86,
monoclonal antibody OKT3, agents blocking the interaction between
CD40 and CD154 (a.k.a. "gp39"), such as antibodies specific for
CD40 and/or CD154, fusion proteins such as etanercept, fusion
proteins constructed from CD40 and/or CD154gp39 (e.g. CD401g and
CD8gp39), inhibitors, such as nuclear translocation inhibitors, of
NF-kappa B function, such as deoxyspergualin (DSG).
[0191] The anti-fungal agents which may be optionally employed in
combination with compounds of formula I of the invention include
fluconazole, miconazole, amphotericin B, and the like.
[0192] The antibiotics which may be optionally employed in
combination with compounds of formula I of the invention include
penicillin, tetracycline, amoxicillin, ampicillin, erythromycin,
doxycycline, vancomycin, minocycline, clindamycin or cefalexin.
[0193] The anti-vascular hyperproliferation agents which may be
optionally employed with compounds of formula I of the invention
include methotrexate, leflunomide, FK506 (tacrolimus, Prograf),
[0194] The hypolipidemic agent or lipid-lowering agent or lipid
modulating agents which may be optionally employed in combination
with the compounds of formula I of the invention may include 1, 2,
3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene
synthetase inhibitors, fibric acid derivatives, ACAT inhibitors,
lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal
Na.sup.+/bile acid cotransporter inhibitors, upregulators of LDL
receptor activity, bile acid sequestrants, and/or nicotinic acid
and derivatives thereof.
[0195] MTP inhibitors employed herein include MTP inhibitors
disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S.
Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No.
5,827,875, U.S. Pat. No. 5,885,983 and U.S. application Ser. No.
09/175,180 filed Oct. 20, 1998, now U.S. Pat. No. 5,962,440.
Preferred are each of the preferred MTP inhibitors disclosed in
each of the above patents and applications.
[0196] All of the above U.S. Patents and applications are
incorporated herein by reference.
[0197] Most preferred MTP inhibitors to be employed in accordance
with the present invention include preferred MTP inhibitors as set
out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No.
5,760,246.
[0198] The most preferred MTP inhibitor is
9-[4-[4-[[2-(2,2,2-trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N--
(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ##STR22##
[0199] The hypolipidemic agent may be an HMG CoA reductase
inhibitor which includes, but is not limited to, mevastatin and
related compounds as disclosed in U.S. Pat. No. 3,983,140,
lovastatin (mevinolin) and related compounds as disclosed in U.S.
Pat. No. 4,231,938, pravastatin and related compounds such as
disclosed in U.S. Pat. No. 4,346,227, simvastatin and related
compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171.
Other HMG CoA reductase inhibitors which may be employed herein
include, but are not limited to, fluvastatin, disclosed in U.S.
Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.
5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.
4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin
(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.
5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in
U.S. Pat. No. 5,260,440, and related statin compounds disclosed in
U.S. Pat. No. 5,753,675, pyrazole analogs of mevalonolactone
derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs
of mevalonolactone derivatives as disclosed in PCT application WO
86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and
derivatives thereof as disclosed in U.S. Pat. No. 4,647,576,
Searle's SC-45355 (a 3-substituted pentanedioic acid derivative)
dichloroacetate, imidazole analogs of mevalonolactone as disclosed
in PCT application WO 86/07054,
3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as
disclosed in French Patent No. 2,596,393, 2,3-disubstituted
pyrrole, furan and thiophene derivatives as disclosed in European
Patent Application No. 0221025, naphthyl analogs of mevalonolactone
as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such
as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin
(lovastatin) as disclosed in European Patent Application No.
0,142,146 A2, and quinoline and pyridine derivatives disclosed in
U.S. Pat. Nos. 5,506,219 and 5,691,322.
[0200] In addition, phosphinic acid compounds useful in inhibiting
HMG CoA reductase suitable for use herein are disclosed in GB
2205837.
[0201] The squalene synthetase inhibitors suitable for use herein
include, but are not limited to, .alpha.-phosphono-sulfonates
disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et
al, J. Med. Chem., Vol. 31, No. 10, pp 1869-1871 (1988), including
isoprenoid (phosphinyl-methyl)phosphonates as well as other known
squalene synthetase inhibitors, for example, as disclosed in U.S.
Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A.,
Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current
Pharmaceutical Design, 2, 1-40 (1996).
[0202] In addition, other squalene synthetase inhibitors suitable
for use herein include the terpenoid pyrophosphates disclosed by P.
Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the
farnesyl diphosphate analog A and presqualene pyrophosphate
(PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem.
Soc., 98, 1291-1293 (1976), phosphinylphosphonates reported by
McClard, R. W. et al, J. Am. Chem. Soc., 1987, 109, 5544 (1987),
and cyclopropanes reported by Capson, T. L., PhD dissertation,
Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17,
40-43, 48-51, Summary (June, 1987).
[0203] Other hypolipidemic agents suitable for use herein include,
but are not limited to, fibric acid derivatives, such as
fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,
clinofibrate and the like, probucol, and related compounds as
disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil
being preferred, bile acid sequestrants such as cholestyramine,
colestipol and DEAE-Sephadex (Secholex.RTM., Policexide.RTM.V) and
cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),
Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil
(HOE-402), tetrahydrolipstatin (THL),
istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin
(Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide
(Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and
CL-283,546 (disubstituted urea derivatives), nicotinic acid
(niacin), acipimox, acifran, neomycin, p-aminosalicylic acid,
aspirin, poly(diallylmethylamine) derivatives such as disclosed in
U.S. Pat. No. 4,759,923, quaternary amine
poly(diallyldimethylammonium chloride) and ionenes such as
disclosed in U.S. Pat. No. 4,027,009, and other known serum
cholesterol lowering agents.
[0204] The hypolipidemic agent may be an ACAT inhibitor such as
disclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe);
"The ACAT inhibitor, Cl-1011 is effective in the prevention and
regression of aortic fatty streak area in hamsters", Nicolosi et
al, Atherosclerosis (Shannon, Irel). 137(1), 77-85 (1998) "The
pharmacological profile of FCE 27677: a novel ACAT inhibitor with
potent hypolipidemic activity mediated by selective suppression of
the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli,
Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a
bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor",
Smith, C., et al, Bioorg. Med. Chem. Lett. 6(1), 47-50 (1996);
"ACAT inhibitors: physiologic mechanisms for hypolipidemic and
anti-atherosclerotic activities in experimental animals", Krause et
al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,
Inflammation: Mediators Pathways 173-98 (1995), Publisher: CRC,
Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic
agents", Sliskovic et al, Curr. Med. Chem. 1(3), 204-25 1994);
"Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as
hypocholesterolemic agents. 6. The first water-soluble ACAT
inhibitor with lipid-regulating activity. Inhibitors of
acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a
series of substituted
N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced
hypocholesterolemic activity", Stout et al, Chemtracts: Org. Chem.
8(6), 359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd).
[0205] The hypolipidemic agent may be an upregulator of LD2
receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd)
and LY295427 (Eli Lilly).
[0206] The hypolipidemic agent may be a cholesterol absorption
inhibitor preferably Schering-Plough's ezetimibe (SCH58235) and
SCH48461 as well as those disclosed in Atherosclerosis 115, 45-63
(1995) and J. Med. Chem. 41, 973 (1998).
[0207] The hypolipidemic agent may be an ileal Na.sup.+/bile acid
cotransporter inhibitor such as disclosed in Drugs of the Future,
24, 425-430 (1999).
[0208] The lipid-modulating agent may be a cholesteryl ester
transfer protein (CETP) inhibitor such as Pfizer's CP 529,414
(WO/0038722 and EP 818448) and Pharmacia's SC-744 and SC-795.
[0209] The ATP citrate lyase inhibitor which may be employed in the
combination of the invention may include, for example, those
disclosed in U.S. Pat. No. 5,447,954.
[0210] Preferred hypolipidemic agents are pravastatin, lovastatin,
simvastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin
and visastatin and ZD-4522.
[0211] The above-mentioned U.S. patents are incorporated herein by
reference. The amounts and dosages employed will be as indicated in
the Physician's Desk Reference and/or in the patents set out
above.
[0212] The compounds of formula I of the invention will be employed
in a weight ratio to the hypolipidemic agent (were present), within
the range from about 500:1 to about 1:500, preferably from about
100:1 to about 1:100.
[0213] The dose administered must be carefully adjusted according
to age, weight and condition of the patient, as well as the route
of administration, dosage form and regimen and the desired
result.
[0214] The dosages and formulations for the hypolipidemic agent
will be as disclosed in the various patents and applications
discussed above.
[0215] The dosages and formulations for the other hypolipidemic
agent to be employed, where applicable, will be as set out in the
latest edition of the Physicians' Desk Reference.
[0216] For oral administration, a satisfactory result may be
obtained employing the MTP inhibitor in an amount within the range
of from about 0.01 mg to about 500 mg and preferably from about 0.1
mg to about 100 mg, one to four times daily.
[0217] A preferred oral dosage form, such as tablets or capsules,
will contain the MTP inhibitor in an amount of from about 1 to
about 500 mg, preferably from about 2 to about 400 mg, and more
preferably from about 5 to about 250 mg, one to four times
daily.
[0218] For oral administration, a satisfactory result may be
obtained employing an HMG CoA reductase inhibitor, for example,
pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or
cerivastatin in dosages employed as indicated in the Physician's
Desk Reference, such as in an amount within the range of from about
1 to 2000 mg, and preferably from about 4 to about 200 mg.
[0219] The squalene synthetase inhibitor may be employed in dosages
in an amount within the range of from about 10 mg to about 2000 mg
and preferably from about 25 mg to about 200 mg.
[0220] A preferred oral dosage form, such as tablets or capsules,
will contain the HMG CoA reductase inhibitor in an amount from
about 0.1 to about 100 mg, preferably from about 0.5 to about 80
mg, and more preferably from about 1 to about 40 mg.
[0221] A preferred oral dosage form, such as tablets or capsules
will contain the squalene synthetase inhibitor in an amount of from
about 10 to about 500 mg, preferably from about 25 to about 200
mg.
[0222] The hypolipidemic agent may also be a lipoxygenase inhibitor
including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole
derivatives as disclosed in WO 97/12615, 15-LO inhibitors as
disclosed in WO 97/12613, isothiazolones as disclosed in WO
96/38144, and 15-LO inhibitors as disclosed by Sendobry et al
"Attenuation of diet-induced atherosclerosis in rabbits with a
highly selective 15-lipoxygenase inhibitor lacking significant
antioxidant properties", Brit. J Pharmacology 120, 1199-1206
(1997), and Cornicelli et al, "15-Lipoxygenase and its Inhibition:
A Novel Therapeutic Target for Vascular Disease", Current
Pharmaceutical Design, 5, 11-20 (1999).
[0223] The compounds of formula I and the hypolipidemic agent may
be employed together in the same oral dosage form or in separate
oral dosage forms taken at the same time.
[0224] The compositions described above may be administered in the
dosage forms as described above in single or divided doses of one
to four times daily. It may be advisable to start a patient on a
low dose combination and work up gradually to a high dose
combination.
[0225] The preferred hypolipidemic agent is pravastatin,
simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin
as well as niacin and/or cholestagel.
[0226] The other antidiabetic agent which may be optionally
employed in combination with the compound of formula I may be 1,2,3
or more antidiabetic agents or antihyperglycemic agents including
insulin secretagogues or insulin sensitizers, or other antidiabetic
agents preferably having a mechanism of action different from the
compounds of formula I of the invention, which may include
biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR .gamma.
agonists, such as thiazolidinediones, aP2 inhibitors, dipeptidyl
peptidase IV (DP4) inhibitors, SGLT2 inhibitors, and/or
meglitinides, as well as insulin, and/or glucagon-like peptide-1
(GLP-1).
[0227] The other antidiabetic agent may be an oral
antihyperglycemic agent preferably a biguanide such as metformin or
phenformin or salts thereof, preferably metformin HCl.
[0228] Where the antidiabetic agent is a biguanide, the compounds
of structure I will be employed in a weight ratio to biguanide
within the range from about 0.001:1 to about 10:1, preferably from
about 0.01:1 to about 5:1.
[0229] The other antidiabetic agent may also preferably be a
sulfonyl urea such as glyburide (also known as glibenclamide),
glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide,
gliclazide or chlorpropamide, other known sulfonylureas or other
antihyperglycemic agents which act on the ATP-dependent channel of
the [1-cells, with glyburide and glipizide being preferred, which
may be administered in the same or in separate oral dosage
forms.
[0230] The compounds of structure I will be employed in a weight
ratio to the sulfonyl urea in the range from about 0.01:1 to about
100:1, preferably from about 0.02:1 to about 5:1.
[0231] The oral antidiabetic agent may also be a glucosidase
inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769)
or miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be
administered in the same or in a separate oral dosage forms.
[0232] The compounds of structure I will be employed in a weight
ratio to the glucosidase inhibitor within the range from about
0.01: 1 to about 100:1, preferably from about 0.05:1 to about
10:1.
[0233] The compounds of structure I may be employed in combination
with a PPAR Y agonist such as a thiazolidinedione oral
anti-diabetic agent or other insulin sensitizers (which has an
insulin sensitivity effect in NIDDM patients) such as troglitazone
(Warner-Lambert's Rezulino, disclosed in U.S. Pat. No. 4,572,912),
rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555
(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570,
englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer,
isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645
(Merck), R-1 19702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440
(Yamanouchi), preferably rosiglitazone and pioglitazone.
[0234] The compounds of structure I will be employed in a weight
ratio to the thiazolidinedione in an amount within the range from
about 0.01: 1 to about 100:1, preferably from about 0.05 to about
10:1.
[0235] The sulfonyl urea and thiazolidinedione in amounts of less
than about 150 mg oral antidiabetic agent may be incorporated in a
single tablet with the compounds of structure I.
[0236] The compounds of structure I may also be employed in
combination with a antihyperglycemic agent such as insulin or with
glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide,
GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No.
5,614,492 to Habener, the disclosure of which is incorporated
herein by reference), as well as AC2993 (Amylin) and LY-315902
(Lilly), which may be administered via injection, intranasal,
inhalation or by transdermal or buccal devices.
[0237] Where present, metformin, the sulfonyl ureas, such as
glyburide, glimepiride, glipyride, glipizide, chlorpropamide and
gliclazide and the glucosidase inhibitors acarbose or miglitol or
insulin (injectable, pulmonary, buccal, or oral) may be employed in
formulations as described above and in amounts and dosing as
indicated in the Physician's Desk Reference (PDR).
[0238] Where present, metformin or salt thereof may be employed in
amounts within the range from about 500 to about 2000 mg per day
which may be administered in single or divided doses one to four
times daily.
[0239] Where present, the thiazolidinedione anti-diabetic agent may
be employed in amounts within the range from about 0.01 to about
2000 mg/day which may be administered in single or divided doses
one to four times per day.
[0240] Where present insulin may be employed in formulations,
amounts and dosing as indicated by the Physician's Desk
Reference.
[0241] Where present GLP-1 peptides may be administered in oral
buccal formulations, by nasal administration or parenterally as
described in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and
5,631,224 which are incorporated herein by reference.
[0242] The other antidiabetic agent may also be a PPAR
.alpha./.gamma. dual agonist such as AR-HO39242 (Astra/Zeneca),
GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those
disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a
Coligand for Peroxisome Proliferation-Activated Receptor Alpha
(PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on
Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes
47, 1841-1847 (1998).
[0243] The antidiabetic agent may be an SGLT2 inhibitor such as
disclosed in U.S. application Ser. No. 09/679,027, filed Oct. 4,
2000 employing dosages as set out therein. Preferred are the
compounds designated as preferred in the above application.
[0244] The antidiabetic agent may be an aP2 inhibitor such as
disclosed in U.S. application Ser. No. 09/391,053, filed Sep. 7,
1999, and in U.S. application Ser. No. 09/519,079, filed Mar. 6,
2000 employing dosages as set out herein. Preferred are the
compounds designated as preferred in the above application.
[0245] The antidiabetic agent may be a DP4 inhibitor such as
disclosed in U.S. application Ser. No. 09/788,173 filed Feb. 16,
2001, WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278
(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A
(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrro-
lidine) (Novartis) (preferred) as disclosed by Hughes et al,
Biochemistry, 38(36), 11597-11603, (1999), TSL-225
(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid
(disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8
1537-1540 (1998), 2-cyanopyrrolidides and 4-cyanopyrrolidides as
disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol.
6, No. 22, pp 1163-1166 and 2745-2748 (1996) employing dosages as
set out in the above references.
[0246] The meglitinide which may optionally be employed in
combination with the compound of formula I of the invention may be
repaglinide, nateglinide (Novartis) or KAD1229 (PF/Kissei), with
repaglinide being preferred.
[0247] The compound of formula I will be employed in a weight ratio
to the meglitinide, PPAR .gamma. agonist, PPAR .alpha./.gamma. dual
agonist, aP2 inhibitor, DP4 inhibitor or SGLT2 inhibitor within the
range from about 0.01: 1 to about 100:1, preferably from about 0.05
to about 10:1.
[0248] The other type of therapeutic agent which may be optionally
employed with a compound of formula I may be 1, 2, 3 or more of an
anti-obesity agent including a beta 3 adrenergic agonist, a lipase
inhibitor, a serotonin (and dopamine) reuptake inhibitor, an aP2
inhibitor, a thyroid receptor agonist and/or an anorectic
agent.
[0249] The beta 3 adrenergic agonist which may be optionally
employed in combination with a compound of formula I may be AJ9677
(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other
known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,
5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677,
L750,355 and CP331648 being preferred.
[0250] The lipase inhibitor which may be optionally employed in
combination with a compound of formula I may be orlistat or ATL-962
(Alizyme), with orlistat being preferred.
[0251] The serotonin (and dopoamine) reuptake inhibitor which may
be optionally employed in combination with a compound of formula I
may be sibutramine, topiramate (Johnson & Johnson) or axokine
(Regeneron), with sibutramine and topiramate being preferred.
[0252] The thyroid receptor agonist which may be optionally
employed in combination with a compound of formula I may be a
thyroid receptor ligand as disclosed in WO97/21993 (U. Cal SF),
WO99/00353 (KaroBio), GB98/284425 (KaroBio), and U.S. Provisional
Application 60/183,223 filed Feb. 17, 2000, with compounds of the
KaroBio applications and the above U.S. provisional application
being preferred.
[0253] The anorectic agent which may be optionally employed in
combination with a compound of formula I may be dexamphetamine,
phentermine, phenylpropanolamine or mazindol, with dexamphetamine
being preferred.
[0254] The various anti-obesity agents described above may be
employed in the same dosage form with the compound of formula I or
in different dosage forms, in dosages and regimens as generally
known in the art or in the PDR.
[0255] The antihypertensive agents which may be employed in
combination with the compound of formula I of the invention include
ACE inhibitors, angiotensin II receptor antagonists, NEP/ACE
inhibitors, as well as calcium channel blockers, .beta.-adrenergic
blockers and other types of antihypertensive agents including
diuretics.
[0256] The angiotensin converting enzyme inhibitor which may be
employed herein includes those containing a mercapto (--S--) moiety
such as substituted proline derivatives, such as any of those
disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned
above, with captopril, that is,
1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred,
and mercaptoacyl derivatives of substituted prolines such as any of
those disclosed in U.S. Pat. No. 4,316,906 with zofenopril being
preferred.
[0257] Other examples of mercapto containing ACE inhibitors that
may be employed herein include rentiapril (fentiapril, Santen)
disclosed in Clin. Exp. Pharmacol. Physiol. 10:131 (1983); as well
as pivopril and YS980.
[0258] Other examples of angiotensin converting enzyme inhibitors
which may be employed herein include any of those disclosed in U.S.
Pat. No. 4,374,829 mentioned above, with
N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,
enalapril, being preferred, any of the phosphonate substituted
amino or imino acids or salts disclosed in U.S. Pat. No. 4,452,790
with
(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-p-
roline or (ceronapril) being preferred, phosphinylalkanoyl prolines
disclosed in U.S. Pat. No. 4,168,267 mentioned above with
fosinopril being preferred, any of the phosphinylalkanoyl
substituted prolines disclosed in U.S. Pat. No. 4,337,201, and the
phosphonamidates disclosed in U.S. Pat. No. 4,432,971 discussed
above.
[0259] Other examples of ACE inhibitors that may be employed herein
include Beecham's BRL 36,378 as disclosed in European Patent
Application Nos. 80822 and 60668; Chugai's MC-838 disclosed in C.A.
102:72588v and Jap. J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS
14824
(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-ox-
o-1-(3S)-benzazepine-1 acetic acid HCl) disclosed in U.K. Patent
No. 2103614 and CGS 16,617
(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-
-benzazepine-1-ethanoic acid) disclosed in U.S. Pat. No. 4,473,575;
cetapril (alacepril, Dainippon) disclosed in Eur. Therap. Res.
39:671 (1986); 40:543 (1986); ramipril (Hoechsst) disclosed in
Euro. Patent No. 79-022 and Curr. Ther. Res. 40:74 (1986); Ru 44570
(Hoechst) disclosed in Arzneimittelforschung 34:1254 (1985),
cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc. Pharmacol.
9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBS Lett.
165:201 (1984); lisinopril (Merck), indalapril (delapril) disclosed
in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed in J.
Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)
disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5): 173 (1986);
perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519
(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No.
4,344,949 and CI925 (Warner-Lambert)
([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-
-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic
acid HCl) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221
(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).
[0260] Preferred ACE inhibitors are captopril, fosinopril,
enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril
and moexipril.
[0261] NEP/ACE inhibitors may also be employed herein in that they
possess neutral endopeptidase (NEP) inhibitory activity and
angiotensin converting enzyme (ACE) inhibitory activity. Examples
of NEP/ACE inhibitors suitable for use herein include those
disclosed in U.S. Pat. Nos. 5,362,727, 5,366,973, 5,225,401,
4,722,810, 5,223,516, 4,749,688, U.S. Pat. No. 5,552,397, U.S. Pat.
No. 5,504,080, U.S. Pat. No. 5,612,359,U.S. Pat. No. 5,525,723,
European Patent Application 0599,444, 0481,522, 0599,444, 0595,610,
European Patent Application 0534363A2, 534,396 and 534,492, and
European Patent Application 0629627A2.
[0262] Preferred are those NEP/ACE inhibitors and dosages thereof
which are designated as preferred in the above patents/applications
which U.S. patents are incorporated herein by reference; most
preferred are omapatrilat, BMS 189,921
([S(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dime-
thyl-7-oxo-1H-azepine-1-acetic acid (gemopatrilat)) and CGS
30440.
[0263] The angiotensin II receptor antagonist (also referred to
herein as angiotensin II antagonist or AII antagonist) suitable for
use herein includes, but is not limited to, irbesartan, losartan,
valsartan, candesartan, telmisartan, tasosartan or eprosartan, with
irbesartan, losartan or valsartan being preferred.
[0264] A preferred oral dosage form, such as tablets or capsules,
will contain the ACE inhibitor or AII antagonist in an amount
within the range from abut 0.1 to about 500 mg, preferably from
about 5 to about 200 mg and more preferably from about 10 to about
150 mg.
[0265] For parenteral administration, the ACE inhibitor,
angiotensin II antagonist or NEP/ACE inhibitor will be employed in
an amount within the range from about 0.005 mg/kg to about 10 mg/kg
and preferably from about 0.01 mg/kg to about 1 mg/kg.
[0266] Where a drug is to be administered intravenously, it will be
formulated in conventional vehicles, such as distilled water,
saline, Ringer's solution or other conventional carriers.
[0267] It will be appreciated that preferred dosages of ACE
inhibitor and AII antagonist as well as other antihypertensives
disclosed herein will be as set out in the latest edition of the
Physician's Desk Reference (PDR).
[0268] Other examples of preferred antihypertensive agents suitable
for use herein include omapatrilat (Vanlev.RTM.) amlodipine
besylate (Norvasc.RTM.), prazosin HCl (Minipress.RTM.), verapamil,
nifedipine, nadolol, diltiazem, felodipine, nisoldipine,
isradipine, nicardipine, atenolol, carvedilol, sotalol, terazosin,
doxazosin, propranolol, and clonidine HCl (Catapres.RTM.).
[0269] Diuretics which may be employed in combination with
compounds of formula I include hydrochlorothiazide, torasemide,
furosemide, spironolactono, and indapamide.
[0270] Antiplatelet agents which may be employed in combination
with compounds of formula I of the invention include aspirin,
clopidogrel, ticlopidine, dipyridamole, abciximab, tirofiban,
eptifibatide, anagrelide, and ifetroban, with clopidogrel and
aspirin being preferred.
[0271] The antiplatelet drugs may be employed in amounts as
indicated in the PDR. Ifetroban may be employed in amounts as set
out in U.S. Pat. No. 5,100,889.
[0272] Antiosteoporosis agents suitable for use herein in
combination with the compounds of formula I of the invention
include parathyroid hormone or bisphosphonates, such as MK-217
(alendronate) (Fosamax.RTM.).
[0273] Dosages employed for the above drugs will be as set out in
the Physician's Desk Reference.
Pharmaceutical Formulations
[0274] The pharmaceutical composition of the invention includes a
pharmaceutically acceptable carrier, adjuvant or vehicle that may
be administered to a subject, together with a compound of the
present invention, and which does not destroy the pharmacological
activity thereof. Pharmaceutically acceptable carriers, adjuvants
and vehicles that may be used in the pharmaceutical compositions of
the present invention include, but are not limited to, the
following: ion exchangers, alumina, aluminum stearate, lecithin,
self-emulsifying drug delivery systems ("SEDDS") such as
d(-tocopherol polyethyleneglycol 1000 succinate), surfactants used
in pharmaceutical dosage forms such as Tweens or other similar
polymeric delivery matrices, serum proteins such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat. Cyclodextrins such as .alpha.-, .beta.- and
.gamma.-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-.beta.-cyclodextrins, or other solubilized
derivatives may also be used to enhance delivery of the modulators
of the present invention.
[0275] The compositions of the present invention may contain other
therapeutic agents as described below, and may be formulated, for
example, by employing conventional solid or liquid vehicles or
diluents, as well as pharmaceutical additives of a type appropriate
to the mode of desired administration (for example, excipients,
binders, preservatives, stabilizers, flavors, etc.) according to
techniques such as those well known in the art of pharmaceutical
formulation.
[0276] The compounds of the invention may be administered by any
suitable means, for example, orally, such as in the form of
tablets, capsules, granules or powders; sublingually; buccally;
parenterally, such as by subcutaneous, intravenous, intramuscular,
or intrasternal injection or infusion techniques (e.g., as sterile
injectable aqueous or non-aqueous solutions or suspensions);
nasally such as by inhalation spray; topically, such as in the form
of a cream or ointment; or rectally such as in the form of
suppositories; in dosage unit formulations containing non-toxic,
pharmaceutically acceptable vehicles or diluents. The compounds of
the invention may, for example, be administered in a form suitable
for immediate release or extended release. Immediate release or
extended release may be achieved by the use of suitable
pharmaceutical compositions including the compounds of the
invention, or, particularly in the case of extended release, by the
use of devices such as subcutaneous implants or osmotic pumps. The
compounds of the invention may also be administered
liposomally.
[0277] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or favoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The present compounds may also be delivered
through the oral cavity by sublingual and/or buccal administration.
Molded tablets, compressed tablets or freeze-dried tablets are
exemplary forms which may be used. Exemplary compositions include
those formulating the compound(s) of the invention with fast
dissolving diluents such as mannitol, lactose, sucrose and/or
cyclodextrins. Also included in such formulations may be high
molecular weight excipients such as celluloses (Avicel) or
polyethylene glycols (PEG). Such formulations may also include an
excipient to aid mucosal adhesion such as hydroxy propyl cellulose
(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy
methyl cellulose (SCMC), maleic anhydride copolymer (e.g.,
Gantrez), and agents to control release such as polyacrylic
copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0278] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which may contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0279] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid. The term
"parenteral" as used herein includes subcutaneous, intracutaneous,
intravenous, intramuscular, intraarticular, intraarterial,
intrasynovial, intrasternal, intrathecal, intralesional and
intracranial injection or infusion techniques.
[0280] Exemplary compositions for rectal administration include
suppositories which may contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquefy and/or dissolve in the rectal cavity to
release the drug.
[0281] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0282] The effective amount of a compound of the present invention
may be determined by one of ordinary skill in the art, and includes
exemplary dosage amounts for an adult human of from about 0.1 to
500 mg/kg of body weight of active compound per day, or between 5
and 2000 mg per day which may be administered in a single dose or
in the form of individual divided doses, such as from 1 to 5 times
per day. It will be understood that the specific dose level and
frequency of dosage for any particular subject may be varied and
will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of
action of that compound, the species, age, body weight, general
health, sex and diet of the subject, the mode and time of
administration, rate of excretion, drug combination, and severity
of the particular condition. Preferred subjects for treatment
include animals, most preferably mammalian species such as humans,
and domestic animals such as dogs, cats and the like.
[0283] A typical capsule for oral administration contains compounds
of structure I (250 mg), lactose (75 mg) and magnesium stearate (15
mg). The mixture is passed through a 60 mesh sieve and packed into
a No. 1 gelatin capsule.
[0284] A typical injectable preparation is produced by aseptically
placing 250 mg of compounds of structure I into a vial, aseptically
freeze-drying and sealing. For use, the contents of the vial are
mixed with 2 mL of physiological saline, to produce an injectable
preparation.
[0285] The compounds of formula (I) of the invention are
glucocorticoid receptor modulators as shown either by their ability
to bind glucocorticoid receptors in GR binding assays, or by their
ability to inhibit AP-1 activity as indicated in cellular
transrespressional assays, and cause none to minimal
transactivation as indicated in cellular transcriptional
assays.
[0286] Examples of the invention have been tested in at least one
of the assays described below and have glucocorticoid receptor
(GR)/Dexamethasone (Dex) inhibition activity (>25%, preferably
>95% at 10 .mu.M) and/or AP-1 inhibition activity (EC.sub.50
less than 15 EM).
[0287] Identical and/or similar assays are described in copending
provisional application No. 60/396,907, filed Jul. 18, 2002 which
is incorporated in its entirety herein by reference.
GR (Dex) Binding Assay
[0288] In order to measure the binding of compounds to Site I on
the glucocorticoid receptor a commercially available kit was used
(Glucocorticoid receptor competitor assay kit, Panvera Co.,
Madison, Wis.). Briefly, a cell lysate containing recombinantly
expressed human full-length glucocorticoid receptor was mixed with
a fluorescently labeled glucocorticoid (4 nM FITC-dexamethasone)
plus or minus test molecule. After one hour at room temperature,
the fluorescence polarization (FP) of the samples were measured.
The FP of a mixture of receptor, fluorescent probe (i.e.
FITC-dexamethasone) and 11 mM dexamethasone represented background
fluorescence or 100% inhibition, whereas, the FP of the mixture
without dexamethasone was taken to be 100% binding. The percentage
inhibition of test molecules were then compared to the sample with
1 mM dexamethasone and expressed as % relative binding activity
with dexamethasone being 100% and no inhibition is 0%. Test
molecules were analyzed in the concentration range from 0.1 nM to
40 .mu.M.
[0289] Site I binding assays for any NHR (Nuclear Hormone Receptor)
are conducted similarly to the above. An appropriate cell lysate or
purified NHR is used as the source of the NHR. The fluorescent
probe and unlabeled competitor are appropriate for the specific
NHR, i.e. are ligands for the specific NHR.
Cellular Transrepressional Assay
[0290] To measure the ability of test molecules to inhibit AP-1
induced transcriptional activity we utilized an A549 cell which was
stably transfected with a plasmid containing 7.times.AP-1 DNA
binding sites (pAP-1-Luc plasmid, Stratagene Co. La Jolla, Calif.)
followed by the gene for luciferase. Cells were activated with 10
ng/ml of phorbol myristic acid (PMA) plus or minus test molecules
for 7 hours. After 7 hours a luciferase reagent was added to
measure luciferase enzymatic activity in the cell. After a 10
minute incubation of luciferase reagent with cells, luminescence
was measured in a TopCount luminescence counter. Repression of AP-1
activity was calculated as the percentage decrease in the signal
induced by PMA alone. Test molecules were analyzed in the
concentration range from 0.1 nM to 40 .mu.M. EC50s were determined
by using standard curve fitting methods such as Excel fit
(Microsoft Co.). An EC50 is the test molecule concentration at
which there is a 50% repression of the maximal inhibition of
transcription, i.e. a 50% reduction of AP-1 activity.
[0291] Other reporters and cell lines also may be used in a
cellular transrepressional assay. A similar assay may be performed
in which NF-.kappa.B activity can be measured. A plasmid containing
NF-.kappa.B DNA binding sites, such as pNF-.kappa.B-Luc,
(Stratagene, LaJolla Calif.), and PMA, or another stimulus, such as
TNF-.alpha. or lipopolysaccharide, is used to activate the
NF-.kappa.B pathway. NF-.kappa.B assays similar to that described
in Yamamoto K., et al., J Biol Chem December 29; 270(52):31315-20
(1995) may be used.
[0292] The cellular transrepressional assays described above may be
used to measure transrepression by any NHR. One of skill in the art
will understand that assays may require the addition of components,
such as a stimulus (eg. PMA, lipopolysaccharide, TNF-.alpha., etc)
which will induce transcription mediated by AP-1 or NF-.kappa.B.
Additionally, AR mediated transrepression may be measured by the
assay described in Palvimo J J, et al. J Biol Chem September 27;
271(39):24151-6 (1996), and PR mediated transrepression may be
measured by the assay described in Kalkhoven E., et al. J Biol Chem
March 15; 271(11):6217-24 (1996).
Abbreviations
[0293] The following abbreviations are employed in the following
Preparations and Examples: [0294] Ph=phenyl [0295] Bn=benzyl [0296]
t-Bu=tertiary butyl [0297] Me=methyl [0298] Et=ethyl [0299]
TMS=trimethylsilyl [0300] TMSN.sub.3=trimethylsilyl azide [0301]
TBS=tert-butyldimethylsilyl [0302] FMOC=fluorenylmethoxycarbonyl
[0303] Boc=tert-butoxycarbonyl [0304] Cbz=carbobenzyloxy or
carbobenzoxy or benzyloxycarbonyl [0305] THF=tetrahydrofuran [0306]
Et.sub.2O=diethyl ether [0307] hex=hexanes [0308] EtOAc=ethyl
acetate [0309] DMF=dimethyl formamide [0310] MeOH=methanol [0311]
EtOH=ethanol [0312] i-PrOH=isopropanol [0313] DMSO=dimethyl
sulfoxide [0314] DME=1,2 dimethoxyethane [0315] DCE=1,2
dichloroethane [0316] HMPA=hexamethyl phosphoric triamide [0317]
HOAc or AcOH=acetic acid [0318] TFA=trifluoroacetic acid [0319]
TFAA=trifluoroacetic anhydride [0320]
i-Pr.sub.2NEt=diisopropylethylamine [0321] Et.sub.3N=triethylamine
[0322] NMM=N-methyl morpholine [0323] DMAP=4-dimethylaminopyridine
[0324] NaBH.sub.4=sodium borohydride [0325] NaBH(OAc).sub.3=sodium
triacetoxyborohydride [0326] DIBALH=diisobutyl aluminum hydride
[0327] LAH or LiAlH.sub.4=lithium aluminum hydride [0328]
n-BuLi=n-butyllithium [0329] LDA=lithium diisopropylamide [0330]
Pd/C=palladium on carbon [0331] PtO.sub.2=platinum oxide [0332]
KOH=potassium hydroxide [0333] NaOH=sodium hydroxide [0334]
LiOH=lithium hydroxide [0335] K.sub.2CO.sub.3=potassium carbonate
[0336] NaHCO.sub.3=sodium bicarbonate [0337]
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene [0338] EDC (or EDC.HCl) or
EDCI (or EDCI.HCl) or EDAC=3-ethyl-3'-(dimethylamino)propyl-
carbodiimide hydrochloride (or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) [0339]
HOBT or HOBT.H.sub.2O=1-hydroxybenzotriazole hydrate [0340]
HOAT=1-Hydroxy-7-azabenzotriazole [0341] BOP
reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate [0342] NaN(TMS).sub.2=sodium
hexamethyldisilazide or sodium bis(trimethylsilyl)amide [0343]
Ph.sub.3P=triphenylphosphine [0344] Pd(OAc).sub.2=Palladium acetate
[0345] (Ph.sub.3P).sub.4Pd.sup.o=tetrakis triphenylphosphine
palladium [0346] DEAD=diethyl azodicarboxylate [0347]
DIAD=diisopropyl azodicarboxylate [0348] Cbz-Cl=benzyl
chloroformate [0349] CAN=ceric ammonium nitrate [0350] SAX=Strong
Anion Exchanger [0351] SCX=Strong Cation Exchanger [0352] Ar=argon
[0353] N.sub.2=nitrogen [0354] min=minute(s) [0355] h or hr=hour(s)
[0356] L=liter [0357] mL=milliliter [0358] .mu.L=microliter [0359]
g=gram(s) [0360] mg=milligram(s) [0361] mol=moles [0362]
mmol=millimole(s) [0363] meq=milliequivalent [0364] RT=room
temperature [0365] sat or sat'd=saturated [0366] aq.=aqueous [0367]
TLC=thin layer chromatography [0368] HPLC=high performance liquid
chromatography [0369] Reverse phase HPLC=reverse phase high
performance liquid chromatography, using a YMC ODS S5 column and a
binary solvent A/solvent B eluents [0370] Solvent A=10% MeOH-90%
H.sub.2O-0.1% TFA [0371] Solvent B=90% MeOH-10% H.sub.2O-0.1% TFA
[0372] LC/MS=high performance liquid chromatography/mass
spectrometry [0373] MS or Mass Spec=mass spectrometry [0374]
NMR=nuclear magnetic resonance [0375] NMR spectral data: s=singlet;
d=doublet; m=multiplet; br=broad; t=triplet [0376] mp=melting
point
EXAMPLES
[0377] The following Examples illustrate embodiments of the
inventive compounds and starting materials, and are not intended to
limit the scope of the claims.
Examples 1 and 2
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-phe-
nylethanol
Isomers A and B
[0378] (1a) p-Toluenesulfonic acid monohydrate (285 mg, 0.015 eq)
was added to a solution of ethyl 2-methylacetoacetate (14.4 g, 100
mmol) and (S)-(-)-.alpha.-methylbenzylamine (13.3 g, 1.1 eq) in
toluene (200 mL). The resultant mixture was heated to reflux with a
Dean-Stark trap for 6 h, cooled to room temperature and
concentrated in vacuo. The residue was purified by distillation
under vacuum to afford the desired enamine (19.3 g, 78%). MS found:
(M+H).sup.+=248.
[0379] (1b) Methyl vinyl ketone (5.93 g, 1.1 eq) was added to a
solution of zinc chloride (525 mg, 0.05 eq) in toluene (200 mL) at
0.degree. C. and the mixture was stirred at that temperature for 1
h. A solution of the enamine from reaction 1a (19.0 g, 76.9 mmol)
in toluene (50 mL) was added to the above mixture dropwise over 1h
at 0.degree. C. The resultant mixture was stirred at 0.degree. C.
for 1 h, treated with 10% acetic acid in water (50 mL) and warmed
to room temperature for 2 h. After addition of ethyl acetate (600
mL), the mixture was washed with water (100 mL), followed by brine
(100 mL). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo. The residue was chromatographed over silica
gel (ethyl acetate-hexane, 0 to 50%) to yield the desired ketoester
(5.20 g, 34%).
[0380] (1c) Piperidine (1.01 g, 0.8 eq) and acetic acid (942 mg,
0.95 eq) were added to the ketoester from reaction 1b (3.20 g, 14.9
mmol) at room temperature. The resultant mixture was heated to
80.degree. C. for 2 h, cooled to room temperature, diluted with
ethyl acetate (300 mL), washed with water (20 mL), followed by
brine (20 mL), dried over MgSO.sub.4 and concentrated in vacuo. The
residue was chromatographed over silica gel (ethyl acetate-hexane,
0 to 50%) to yield the desired Hagemann's ester (2.30 g, 79%),
which was found to be 70% e.e. based on chiral HPLC analysis (AS
column). MS found: (M+H).sup.+=197.
[0381] (1d) Ethanol (0.1 mL) was added to a mixture of the ester
from reaction 1c (2.00 g, 10.2 mmol), ethyl formate (1.21 g, 1.6
eq), sodium (282 mg, 1.2 eq) in dry ether (50 mL) at room
temperature. After 2 h at room temperature, additional ethanol (0.3
mL) was added and the mixture stirred at room temperature for
additional 3 h. Following addition of water (20 mL), the ether
layer was separated and washed with water (3.times.10 mL). The
combined aqueous layer was adjusted pH=2.about.3 with 1N HCl and
extracted with ethyl acetate (3.times.80 mL). The combined organic
phase was washed with water (30 mL), followed by brine (30 mL),
dried over MgSO.sub.4 and concentrated in vacuo. The residue was
chromatographed over silica gel (ethyl acetate-hexane, 0 to 50%) to
yield the desired aldehyde (1.70 g, 74%). MS found:
(M+H).sup.+=225.
[0382] (1e) Sodium acetate (685 mg, 1.1 eq) was added to a solution
of the aldehyde from reaction 1d (1.70 g, 7.59 mmol) and
4-fluorophenylhydrazine hydrochloride (1.36 g, 1.1 eq) in acetic
acid (20 mL) at room temperature. After 4 h at rt, the mixture was
carefully quenched with saturated sodium carbonate (300 mL) and
extracted with ethyl acetate (3.times.200 mL). The combined organic
phase was washed with brine (100 mL), dried over MgSO.sub.4 and
concentrated in vacuo. The residue was chromatographed over silica
gel (ethyl acetate-hexane, 0 to 50%) yielded the desired ester
(2.05 g, 86%). MS found: (M+H).sup.+=315.
[0383] (1f) A 1.5 M solution of DIBAL in toluene (7.64 mL, 1.8 eq)
was added dropwise to a solution of the ester from reaction 1e
(2.00 g, 6.37 mmol) in dichloromethane (80 mL) at -78.degree. C.
over 0.5 h. After 0.5 h at -78.degree. C., the mixture was quenched
with methanol (10 mL), warmed to room temperature, diluted with
ethyl acetate (500 mL), washed with water (2.times.80 mL), followed
by brine (80 mL), dried over MgSO.sub.4 and concentrated in vacuo.
The residue was chromatographed over silica gel (ethyl
acetate-hexane, 0 to 50%) to yield the desired aldehyde (1.15 g,
67%). MS found: (M+H).sup.+=271.
[0384] (1g) A 1.0 M THF solution of sodium bis(trimethylsilyl)amide
(10.7 mL, 2.9 eq) was added dropwise to a solution of
(methoxymethyl)triphenylphosphonium chloride (3.81 g, 3.0 eq) in
THF (50 mL) at -78.degree. C. After 1 h at -78.degree. C., a
solution of the aldehyde from reaction 1f (1.00 g, 3.70 mmol) in
THF (5 mL) was added dropwise. After 2 h -78.degree. C., the
mixture was quenched with water (20 mL), diluted with ether (300
mL), washed with water (50 mL), followed by brine (50 mL), dried
over MgSO.sub.4 and concentrated in vacuo. The residue was
chromatographed over silica gel (ethyl acetate-hexane, 0 to 50%) to
yield the desired enol ether (760 mg, 61%). MS found:
(M+H).sup.+=298.
[0385] (1h) Pyridinium p-toluenesulfonate (1.23 g, 2.0 eq) was
added to a solution of the enol ether from reaction 1g (730 mg,
2.45 mmol) in THF/H.sub.2O (25 mL, 10:1). After 12 h at reflux, the
mixture was cooled to room temperature, diluted with ether (300
mL), washed with water (50 mL), followed by brine (50 mL), dried
over MgSO.sub.4 and concentrated in vacuo. The residue was
chromatographed over silica gel (ethyl acetate-hexane, 0 to 50%) to
yield the aldehyde (630 mg, 91%), which was purified using chiral
OJ column (isocratic, i-PrOH/heptane, 20%) to provide the major
enantiomer as the desired aldehyde (400 mg, >98% ee). MS found:
(M+H).sup.+=285.
[0386] (1i) A solution of the homochiral aldehyde from reaction 1h
(30 mg, 0.106 mmol) in THF (2 mL) was added to 1.0 M solution of
phenylmagnesium bromide in THF (1.06 mL, 10 eq) at room
temperature. After 0.5 h, the mixture was quenched with water (1
mL), diluted with ethyl acetate (60 mL), washed with water (5 mL),
followed by brine (5 mL), dried over MgSO.sub.4 and concentrated in
vacuo. The residue was chromatographed over silica gel (ethyl
acetate-hexane, 0 to 60%) to yield the desired alcohol as a mixture
of two diastereomers (30 mg), which was separated by chiral AD
column (isocratic, i-PrOH/heptane, 20%) to yield Example 1 (12 mg,
31%, isomer A, faster eluent) and Example 2 (11 mg, 29%, isomer B,
slower eluent). MS found: (M+H).sup.+=263.
Examples 3 and 4
1-(4-fluorophenyl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazol-5-yl]ethanol
Isomers A and B
[0387] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 3 (7 mg, 17%, isomer A,
faster eluent on chiral AD column) and Example 4 (15 mg, 37%,
isomer B, slower eluent). MS found: (M+H).sup.+=338 1.
Examples 5 and 6
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-[4--
(methyloxy)phenyl]ethanol
Isomers A and B
[0388] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 5 (13 mg, 31%, isomer A,
faster eluent on chiral AD column) and Example 6 (12 mg, 29%,
isomer B, slower eluent). MS found: (M+H).sup.+=393.
Examples 7 and 8
1-(4-fluorophenyl)-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazol-5-yl]propan-2-ol
Isomers A and B
[0389] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 7 (10 mg, 24%, isomer A,
faster eluent on chiral AD column) and Example 8 (10 mg, 24%,
isomer B, slower eluent). MS found: (M+H).sup.+=395.
Examples 9 and 10
1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]hex-5--
en-2-ol
Isomers A and B
[0390] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 9 (7 mg, 19%, isomer A,
faster eluent on chiral AD column) and Example 10 (9 mg, 25%,
isomer B, slower eluent). MS found: (M+H).sup.+=341.
Examples 11 and 12
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-nap-
hthalen-1-ylethanol
Isomers A and B
[0391] In an analogous procedure to reaction 1i with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 11 (12 mg, 27%, isomer A,
faster eluent on chiral OD column) and Example 12 (15 mg, 27%,
isomer B, slower eluent). MS found: (M+H).sup.+=413.
Examples 13 and 14
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-nap-
hthalen-2-ylethanol
Isomers A and B
[0392] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 13 (11 mg, 25%, isomer A,
faster eluent on chiral OD column) and Example 14 (11 mg, 25%,
isomer B, slower eluent). MS found: (M+H).sup.+=413.
Examples 15 and 16
1-biphenyl-2-yl-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-ind-
azol-5-yl]ethanol
Isomers A and B
[0393] A 1.7 M hexane solution of tert-butyllithium (1.24 mL, 20
eq) was added to a solution of 2-bromobiphenyl (247 mg, 10 eq) in
ether (10 ml) at 0.degree. C. and the mixture was stirred at room
temperature for 0.5 h. A solution of the homochiral aldehyde from
reaction 1h (30 mg, 0.106 mmol) in ether (2 mL) was added. After
0.5 h at room temperature, the mixture was quenched with saturated
NH.sub.4Cl (2 mL), diluted with ethyl acetate (60 mL), washed with
water (5 mL), followed by brine (5 mL), dried over MgSO.sub.4 and
concentrated in vacuo. The residue was chromatographed over silica
gel (ethyl acetate-hexane, 0 to 60%) to yield the desired alcohol
as a mixture of two diastereomers (29 mg), which was subsequently
separated by chiral AD column (isocratic, i-PrOH/heptane, 15%) to
yield Example 15 (10 mg, 22%, isomer A, faster eluent) and Example
16 (10 mg, 22%, isomer B, slower eluent). MS found:
(M+H).sup.+=439.
Examples 17 and 18
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(3--
thienyl)ethanol
Isomers A and B
[0394] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 17 (12 mg, 31%, isomer A,
faster eluent on chiral OD column) and Example 18 (12 mg, 31%,
isomer B, slower eluent). MS found: (M+H).sup.+=369.
Examples 19 and 20
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-(2--
thienyl)ethanol
Isomers A and B
[0395] In an analogous procedure to reaction 1i, with appropriate
starting materials, the homochiral aldehyde from reaction 1h (30
mg, 0.106 mmol) was converted to Example 19 (10 mg, 26%, isomer A,
faster eluent on chiral AD column) and Example 20 (10 mg, 26%,
isomer B, slower eluent). MS found: (M+H).sup.+=369.
Examples 21 and 22
1-(1-benzothien-3-yl)-2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro--
1H-indazol-5-yl]ethanol
Isomers A and B
[0396] In an analogous procedure to the synthesis of Examples 15
& 16, with appropriate starting materials, the homochiral
aldehyde from reaction 1h (30 mg, 0.106 mmol) was converted to
Example 21 (13 mg, 29%, isomer A, faster eluent on chiral OD
column) and Example 22 (13 mg, 29%, isomer B, slower eluent). MS
found: (M+H).sup.+=419.
Example 23
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]ethano-
l
[0397] Sodium borohydride (5.3 mg, 4.0 eq) was added to a solution
of the homochiral aldehyde from reaction 1h (10 mg, 0.035 mmol) in
methanol (1 mL) at 0.degree. C. After 0.5 h at 0.degree. C., the
mixture was quenched with saturated NH.sub.4Cl (1 mL), diluted with
ethyl acetate (60 mL), washed with water (5 mL), followed by brine
(5 mL), dried over MgSO.sub.4 and concentrated in vacuo. The
residue was chromatographed over silica gel (ethyl acetate-hexane,
20 to 70%) to yield Example 23 (8.0 mg, 79%). MS found:
(M+H).sup.+=287.
Example 24
2-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-1-phe-
nylethanone
[0398] 4-Methylmorpholine (63 mg, 1.5 eq) was added to a solution
of the diastereomeric mixture of the alcohol from reaction 1i (150
mg, 0.414 mmol) in dichloromethane (5 mL) at 0.degree. C. After 5
minutes, TPAP (145 mg, 1.0 eq) was added. The mixture was stirred
at 0.degree. C. for 1 h, diluted with ethyl acetate (100 mL),
washed with water (10 mL), followed by brine (10 mL), dried over
MgSO.sub.4 and concentrated in vacuo. The residue was
chromatographed over silica gel (ethyl acetate-hexane, 10 to 50%)
to yield Example 24 (125 mg, 84%). MS found: (M+H).sup.+=361.
Examples 25 and 26
1-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl]-2-phe-
nylpropan-2-ol
Isomers A and B
[0399] A 1.5 M ether solution of methyllithium (1.0 mL, 15 eq) was
added to a solution of the ketone from Example 24 (36 mg, 0.100
mmol) in THF (2 mL) at 0.degree. C. After 0.5 h at 0.degree. C.,
the mixture was quenched with water (1 mL), diluted with ethyl
acetate (60 mL), washed with water (5 mL), followed by brine (5
mL), dried over MgSO.sub.4 and concentrated in vacuo. The residue
was chromatographed over silica gel (ethyl acetate-hexane, 10 to
60%) to yield the desired alcohol as a mixture of two diastereomers
(24 mg), which was subsequently separated by chiral OD column
(isocratic, i-PrOH/heptane, 15%) to yield Example 25 (10 mg, 27%,
isomer A, faster eluent) and Example 26 (3.5 mg, 9%, isomer B,
slower eluent). MS found: (M+H).sup.+=377.
Examples 27 and 28
1,1,1-trifluoro-3-[(5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-ind-
azol-5-yl]-2-phenylpropan-2-ol
Isomers A and B
[0400] (Trifluoromethyl)trimethylsilane (142 mg, 10 eq) and
tetramethylammonium fluoride (1 mg, 0.1 eq) were added to a
solution of the ketone from Example 24 (36 mg, 0.100 mmol) in THF
(2 mL) at room temperature. After 12 h at room temperature, 40%
aqueous HF (1 mL) was added. The mixture heated to 50.degree. C.
for 4 h, cooled to room temperature, diluted with ethyl acetate (60
mL), washed with water (5 mL), followed by brine (5 mL), dried over
MgSO.sub.4 and concentrated in vacuo. The residue was
chromatographed over silica gel (ethyl acetate-hexane, 10 to 60%)
to yield the desired alcohol as a mixture of two diastereomers (10
mg), which was subsequently separated by chiral AD column
(isocratic, i-PrOH/heptane, 8%) to yield Example 27 (3.5 mg, 8%,
isomer A, faster eluent) and Example 28 (3.5 mg, 8%, isomer B,
slower eluent). MS found: (M+H).sup.+=431.
Examples 29 and 30
2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-
-yl]-1-phenylethanol
Isomers A and B
[0401] (29a) Potassium carbonate (9.11 g, 1.1 eq) was added to a
mixture of ethyl 3-cyclopropyl-3-oxopropanoate (9.36 g, 60.0 mmol)
and iodomethane (8.95 g, 1.05 eq) in acetone (200 mL) at room
temperature. The mixture was stirred at room temperature for 24 h,
then filtered and the filtrate was concentrated. The residue was
dissolved in ether (300 mL), washed with water (30 mL), followed by
brine (30 mL), dried over MgSO.sub.4 and concentrated to yield the
desired the ester as crude oil (9.80 g). MS found:
(M+Na).sup.+=193.
[0402] (29b) The ester from reaction 29a (9.80 g, 60.0 mmol) and
methyl vinyl ketone (4.63 g, 1.1 eq) were added to a suspension of
sodium hydride (72 mg, 0.03 eq, 60%) in benzene (50 mL) at room
temperature. After 3 h at room temperature, the mixture was
quenched with water (10 mL), diluted with ethyl acetate (300 mL),
washed with water (30 mL), followed by brine (5 mL), dried over
MgSO.sub.4 and concentrated. The residue was dissolved in acetic
acid (3.0 mL) and piperidine (4.0 mL) and the solution was heated
to 80.degree. C. for 5 h. After cooling to room temperature, the
mixture was diluted with ethyl acetate (600 mL), washed with water
(50 mL), followed by brine (50 mL), dried over MgSO.sub.4 and
concentrated. The residue was purified by distillation under
reduced pressure to yield the desired Hagemann's ester (7.20 g,
54%). MS found: (M+H).sup.+=223.
[0403] (29c) Using a procedure analogous to reaction 1d with
appropriate starting materials, the ester from reaction 29b (7.00
g, 31.5 mmol) was converted to the desired aldehyde as a crude oil
(7.70 g). MS found: (M+H).sup.+=251.
[0404] (29d) Using a procedure analogous to reaction J, with
appropriate starting materials, the aldehyde from reaction 29c
(7.70 g, 31.5 mmol) was converted to the desired ester (7.50 g,
70%). MS found: (M+H).sup.+=341.
[0405] (29e) Using a procedure analogous to reaction 1f, with
appropriate starting materials, the ester from reaction 29d (7.00
g, 20.6 mmol) was converted to the desired aldehyde (4.30 g, 70%).
MS found: (M+H).sup.+=297.
[0406] (29f) Using a procedure analogous to reaction 1g, with
appropriate starting materials, the aldehyde from reaction 29e
(2.00 g, 6.75 mmol) was converted to the desired enol ether (2.00
g, 91%). MS found: (M+H).sup.+=325.
[0407] (29g) Using a procedure analogous to reaction 1h, with
appropriate starting materials, the enol ether from reaction 29f
(2.00 g, 6.17 mmol) was converted to the desired aldehyde (1.20 g,
62%). MS found: (M+H).sup.+=311. A portion of the racemic aldehyde
(500 mg) was subsequently separated by chiral OJ column (isocratic,
i-PrOH/heptane, 10%) to yield enantiomer A (200 mg, 40% yield,
>98% ee, faster eluent) and enantiomer B (200 mg, 40% yield,
>95% ee, slower eluent).
[0408] (29h) Using a procedure analogous to reaction 1i, with
appropriate starting materials, the enantiomer A of the aldehyde
from reaction 29g (30 mg, 0.097 mmol) was converted to the desired
alcohol as a mixture of two diastereomers (25 mg), which was
subsequently separated by chiral OD column (isocratic,
i-PrOH/heptane, 15%) to yield Example 29 (9.0 mg, 24%, faster
eluent) and Example 30 (8.0 mg, 21%, slower eluent). MS found:
(M+H).sup.+=389.
Examples 31 and 32
2-[(5S)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-
-yl]-1-phenylethanol
Isomers A and B
[0409] Using a procedure analogous to reaction 1i with appropriate
starting materials, the enantiomer B of the aldehyde from reaction
29g (30 mg, 0.097 mmol) was converted to the desired alcohol as a
mixture of two diastereomers (25 mg), which was subsequently
separated by chiral AD column (isocratic, i-PrOH/heptane, 15%) to
yield Example 31 (10.0 mg, 27%, faster eluent) and Example 32 (9.0
mg, 24%, slower eluent). MS found: (M+H).sup.+=389.
Examples 33 and 34
2-[(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-
-yl]-1-(2-thienyl)ethanol
Isomers A and B
[0410] Using a procedure analogous to reaction 1i, with appropriate
starting materials, the enantiomer A of the aldehyde from reaction
29g (30 mg, 0.097 mmol) was converted to the desired alcohol as a
mixture of two diastereomers (25 mg), which was subsequently
separated by chiral OD column (isocratic, i-PrOH/heptane, 10%) to
yield Example 33 (10.0 mg, 26%, faster eluent) and Example 34 (10.0
mg, 26%, slower eluent). MS found: (M+H).sup.+=395.
Example 35
(5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-phenylethyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazole
[0411] Sodium hydride (5.0 mg, 3.0 eq, 60% in mineral oil) was
added to the alcohol from Example 1 (15 mg, 0.041 mmol) and
iodomethane (17.6 mg, 3.0 eq) in DMF (1 mL) at room temperature.
The resultant mixture was heated to 45.degree. C. for 1 h, cooled
to room temperature, and carefully quenched with water (1 mL).
After addition of EtOAc (60 mL), the mixture was washed with water
(10 mL), brine (10 mL), dried (MgSO.sub.4) and concentrated. Silica
gel column chromatography (EtOAc-hexane, 0 to 30%) yielded Example
35 (11.0 mg, 71%). MS found: (M+H).sup.+=377.
Example 36
(5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydr-
o-1H-indazole
[0412] Using a procedure analogous to Example 35, the alcohol from
Example 1 (100 mg, 0.276 mmol) was reacted with iodoethane to give
Example 36 (95.0 mg, 88%). MS found: (M+H).sup.+=391.
Example 37
(5R)-5-(2-(benzyloxy)-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-d-
ihydro-1H-indazole
[0413] Sodium hydride (20 mg, 60% in mineral oil) was added to the
alcohol from Example 1 (19 mg, 0.0525 mmol) and benzyl bromide
(42.8 mg, 5 eq) in DMF (1 mL) at room temperature. The resultant
mixture was stirred at room temperature for 1 h, quenched with
saturated NH.sub.4Cl (5 mL) and water (5 mL), and extracted with
30% EtOAc/hexane (3.times.10 mL). The combined extracts were washed
with brine (2 mL), dried (MgSO.sub.4) and concentrated. Silica gel
column chromatography (EtOAc-hexane, 0 to 20%) yielded Example 37
(22.4 mg, 94%). MS found: (M+H).sup.+=453.
Example 38
(5R)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-phenyl-2-propoxyethyl)-4,5-dihyd-
ro-1H-indazole
[0414] In an analogous procedure to the synthesis of Examples 35,
Example 1 (8.6 mg, 0.024 mmol) was reacted with 1-bromopropane to
give Example 38 (1.8 mg, 19%). MS found: (M+H).sup.+=405.
Example 39
(5R)-5-(2-(allyloxy)-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole
[0415] In an analogous procedure to the synthesis of Examples 35,
Example 1 (8.0 mg, 0.022 mmol) was reacted with allyl bromide to
give Example 39 (5.4 mg, 61%). MS found: (M+H).sup.+=403.
Example 40
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-phen-
ylethyl methylcarbamate
[0416] A CH.sub.2Cl.sub.2 (0.5 mL) solution of Example 1 (5 mg,
0.014 mmol), methyl isocyanate (0.103 mL) and triethylamine (0.019
mL, 10 eq) was heated in a sealed tube at 80.degree. C. for 6 h.
The crude material was purified by flash column chromatography
(0-55% EtOAc-hexanes) to give Example 40 (4.8 mg, 84%). MS found:
(M+H).sup.+=420.
Example 41
(5R)-1-(4-fluorophenyl)-5-(2-isopropoxy-2-phenylethyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole
[0417] Iron(III) perchlorate (6.0 mg, 0.2 eq) was added to the
alcohol from Example 1 (30 mg, 0.083 mmol) in 2-propanol (2 mL).
The resultant mixture was heated to 45.degree. C. for 72 h and
cooled to room temperature. After addition of EtOAc (100 mL), the
mixture was washed with water (10 mL), brine (10 mL), dried
(MgSO.sub.4) and concentrated. Silica gel column chromatography
(EtOAc-hexane, 0 to 30%) yielded Example 41 (20.0 mg, 60%). MS
found: (M+H).sup.+=405.
Example 42
(5R)-5-(2-cyclobutoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-d-
ihydro-1H-indazole
[0418] In an analogous procedure to the synthesis of Examples 41,
Example 1 (8.5 mg, 0.023 mmol) was reacted with cyclobutanol to
give Example 42 (5.6 mg, 58%). MS found: (M+H)+=417.
Examples 43 and 44
(5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(naphthalen-1-yl)ethyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole
[0419] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (30 mg, 0.106 mmol) was reacted with
1-naphthylmagnesium bromide to give a 1:1 mixture of alcohols (38.5
mg, 88%). Then using a procedure analogous to Example 35, the
alcohols were converted to the desired ether as a mixture of two
diastereomers (30 mg). Separation by chiral OD column (isocratic,
i-PrOH/heptane, 5%) gave Examples 43 (9.0 mg, 24% isomer A, faster
eluent) and 44 (10 mg, 27%, isomer B, slower eluent). MS found:
(M+H)+=427.
Example 45
(5R)-1-(4-fluorophenyl)-5-(2-(4-fluorophenyl)-2-methoxyethyl)-5,6-dimethyl-
-4,5-dihydro-1H-indazole
[0420] Using a procedure analogous to Example 35, the alcohol from
Example 3 (25.0 mg, 0.066 mmol) was reacted with iodomethane to
Example 45 (16.0 mg, 62%). MS found: (M+H).sup.+=395.
Example 46
(5R)-5-(2-ethoxy-2-(4-fluorophenyl)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole
[0421] Using a procedure analogous to Example 35, the alcohol from
Example 3 (25.0 mg, 0.066 mmol) was reacted with iodoethane to give
Example 46 (20.0 mg, 74%). MS found: (M+H)+=409.
Example 47
(5R)-6-cyclopropyl-1-(4-fluorophenyl)-5-(2-methoxy-2-phenylethyl)-5-methyl-
-4,5-dihydro-1H-indazole
[0422] Using a procedure analogous to Example 35, the alcohol from
Example 30 (20.0 mg, 0.052 mmol) was converted to Example 47 (6.0
mg, 29%). MS found: (M+H)+=403.
Examples 48 and 49
1-(biphenyl-3-yl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-in-
dazol-5-yl)ethanol
[0423] In an analogous procedure to Examples 15 and 16, the
homochiral aldehyde from reaction 1h (30 mg, 0.106 mmol) was
reacted with 3-bromobiphenyl to give Examples 48 (10 mg, 22%,
isomer A, faster eluent on chiral AD column) and 49 (10 mg, 22%,
isomer B, slower eluent). MS found: (M+H)+=439.
Examples 50 and 51
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-m-to-
lylethanol
[0424] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (60 mg, 0.211 mmol) was reacted with
3-methylphenylmagnesium bromide to give Examples 50 (17 mg, 21%,
isomer A, faster eluent on chiral OD column) and 51 (17 mg, 21%,
isomer B, slower eluent). MS found: (M+H)+=377.
Example 52
(5R)-5-(2-ethoxy-2-m-tolylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazole
[0425] Using a procedure analogous to Example 35, the alcohol from
Example 51 (12.0 mg, 0.032 mmol) was converted reacted with
iodoethane to give Example 52 (8.0 mg, 62%). MS found:
(M+H).sup.+=405.
Examples 53 and 54
1-(3-fluorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl)ethanol
[0426] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
3-fluorophenylmagnesium bromide to give Examples 53 (14 mg, 26%,
isomer A, faster eluent on chiral OD column) and 54 (11 mg, 21%,
isomer B, slower eluent). MS found: (M+H)+=338 1.
Example 55
(5R)-5-(2-ethoxy-2-(3-fluorophenyl)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole
[0427] Using a procedure analogous to Example 35, the alcohol from
Example 54 (5.0 mg, 0.013 mmol) was reacted with iodoethane to give
Example 55 (4.0 mg, 75%). MS found: (M+H).sup.+=409.
Examples 56 and 57
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-m-
ethoxyphenyl)ethanol
[0428] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
2-methoxyphenylmagnesium bromide to give Examples 56 (14 mg, 25%,
isomer A, faster eluent on chiral OD column) and 57 (9.0 mg, 16%,
isomer B, slower eluent). MS found: (M+H).sup.+=393.
Example 58
(5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-(2-methoxyphenyl)ethyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole
[0429] Using a procedure analogous to Example 35, the alcohol from
Example 57 (15 mg, 0.038 mmol) was reacted with iodomethane to give
Example 58 (9.0 mg, 58%). MS found: (M+H).sup.+=407.
Examples 59 and 60
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-o-to-
lylethanol
[0430] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
2-methylphenylmagnesium bromide to give Examples 59 (15 mg, 28%,
isomer A, faster eluent on chiral AD column) and 60 (15 mg, 28%,
isomer B, slower eluent). MS found: (M+H).sup.+=377.
Example 61
(5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5-dihy-
dro-1H-indazole
[0431] Using a procedure analogous to Example 35, the alcohol from
Example 59 (8.0 mg, 0.021 mmol) was reacted with iodomethane to
give Examples 61 (3.0 mg, 37%). MS found: (M+H).sup.+=391.
Example 62
(5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5-dihy-
dro-1H-indazole
[0432] Using a procedure analogous to Example 35, the alcohol from
Example 60 (5.0 mg, 0.013 mmol) was reacted with iodomethane to
give Examples 62 (3.0 mg, 59%). MS found: (M+H).sup.+=391.
Example 63
(5R)-5-(2-ethoxy-2-o-tolylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazole
[0433] Using a procedure analogous to Example 35, the alcohol from
Example 59 (22 mg, 0.059 mmol) was reacted with iodoethane to give
Examples 63 (8.0 mg, 34%). MS found: (M+H).sup.+=405.
Example 64
(5R)-1-(4-fluorophenyl)-5-(2-methoxy-2-o-tolylethyl)-5,6-dimethyl-4,5,6,7--
tetrahydro-1H-indazole
[0434] A mixture of the ether from Example 61 (20 mg, 0.051 mmol)
and palladium on carbon (5 mg) in methanol (4 mL) was stirred under
H.sub.2 balloon at room temperature for 4 h. The mixture was
filtered and the filtrate was concentrated to yield Example 64 as a
5:1 mixture of two diastereomers (14 mg, 70%). MS found:
(M+H).sup.+=393.
Examples 65 and 66
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-m-
ethoxyphenyl)ethanol
[0435] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
3-methoxyphenylmagnesium bromide to give Examples 65 (15 mg, 27%,
isomer A, faster eluent on chiral OD column) and 66 (15 mg, 27%,
isomer B, slower eluent). MS found: (M+H).sup.+=393.
Examples 67 and 68
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(3-m-
ethylthiophen-2-yl)ethanol
[0436] In an analogous procedure to reaction 1i the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
3-methyl-2-thienylmagnesium bromide to give Examples 67 (12 mg,
22%, isomer A, faster eluent on chiral AD column) and 68 (14 mg,
26%, isomer B, slower eluent). MS found: (M+H).sup.+=383.
Examples 69 and 70
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(5-m-
ethylthiophen-2-yl)ethanol
[0437] In an analogous procedure to reaction 1i the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
5-methyl-2-thienylmagnesium bromide to give Examples 69 (14 mg,
26%, isomer A, faster eluent on chiral OD column) and 70 (10 mg,
19%, isomer B, slower eluent). MS found: (M+H).sup.+=383.
Examples 71 and 72
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(thi-
azol-2-yl)ethanol
[0438] A 1.6 M hexane solution of butyllithium (0.78 mL, 11 eq) was
added to a solution of thiazole (120 mg, 10 eq) in ether (5 ml) at
-78.degree. C. After 0.5 h at -78.degree. C., a solution of the
homochiral aldehyde from reaction 1h (40 mg, 0.141 mmol) in ether
(1 mL) was added. The mixture was stirred at ambient temperature
for 0.5 h, quenched with saturated NH.sub.4Cl (2 mL), diluted with
EtOAc (60 mL), washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. Silica gel column chromatography
(EtOAc-hexane, 30 to 100%) yielded the desired alcohol as a mixture
of two diastereomers (14 mg), which was separated by chiral AD
column (isocratic, i-PrOH/heptane/Diethylamine, 10/90/0.1) to give
Examples 71 (7.0 mg, 13%, isomer A, faster eluent) and 72 (3.5 mg,
6.5%, isomer B, slower eluent). MS found: (M+H).sup.+=370.
Examples 73 and 74
1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)but-3-y-
n-2-ol
[0439] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
ethynylmagnesium bromide to give Examples 73 (10 mg, 23%, isomer A,
faster eluent on chiral OD column) and 74 (6 mg, 13%, isomer B,
slower eluent). MS found: (M+H).sup.+=311.
Examples 75 and 76
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(pyr-
idin-2-yl)ethanol
[0440] A 2.0 M THF solution of iso-PrMgCl (0.70 mL, 10 eq) was
added to a solution of 2-bromopyridine (223 mg, 10 eq) in THF (2
ml) at room temperature. After 2 h, a solution of the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) in THF (1 mL) was
added. The mixture was stirred at room temperature for 24 h,
quenched with saturated NH.sub.4Cl (2 mL), diluted with EtOAc (60
mL), washed with water (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. Silica gel column chromatography (EtOAc-hexane, 0 to
50%) yielded the desired alcohol as a mixture of two diastereomers
(14 mg), which was separated by chiral OD column (isocratic,
i-PrOH/heptane, 20%) to give Examples 75 (6.0 mg, 12%, isomer A,
faster eluent) and 76 (5.0 mg, 10%, isomer B, slower eluent). MS
found: (M+H).sup.+=364.
Example 77
(R)-5-(2-ethoxy-2-(pyridin-2-yl)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-
-dihydro-1H-indazole
[0441] Using a procedure analogous to Example 35, the diastereomer
mixture of the alcohols from Examples 75 and 76 (53 mg, 0.146 mmol)
was reacted with iodoethane to give Example 77 as a 1:2 mixture of
two diastereomers (20 mg, 35%). MS found: (M+H).sup.+=392.
Examples 78 and 79
2-(2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-h-
ydroxyethyl)pyridine 1-oxide
[0442] 3-chloroperoxybenzoic acid (28 mg, 1.5 eq) was added to a
solution of the diastereomer mixture of the alcohols from Examples
75 and 76 in chloroform (3 mL) at room temperature. After 3 h, the
mixture was quenched with saturated NaHCO.sub.3 (1 mL), diluted
with EtOAc (60 mL), washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. Reverse phase HPLC purification
(MeOH-water, 50 to 100%) yielded the desired N-oxide as a mixture
of two diastereomers (5 mg), which was separated by chiral OD
column (isocratic, i-PrOH/heptane, 15%) to give Examples 78 (1.3
mg, 3%, isomer A, faster eluent) and 79 (1.5 mg, 4%, isomer B,
slower eluent). MS found: (M+H).sup.+=380.
Examples 80 and 81
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(pyr-
idin-3-yl)ethanol
[0443] In an analogous procedure to Examples 75 and 76, the
homochiral aldehyde from reaction 1h (40 mg, 0.141 mmol) was
reacted with 3-bromopyridine to give Examples 80 (4 mg, 8%, isomer
A, faster eluent on chiral AD column) and 81 (6 mg, 12%, isomer B,
slower eluent). MS found: (M+H).sup.+=364.
Examples 82 and 83
1-(2,6-dimethylphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro--
1H-indazol-5-yl)ethanol
[0444] In an analogous procedure to reaction 1the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
2,6-dimethylphenylmagnesium bromide to give Examples 82 (15 mg,
27%, isomer A, faster eluent on chiral OD column) and 83 (15 mg,
27%, isomer B, slower eluent). MS found: (M+H).sup.+=391.
Examples 84 and 85
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-m-
ethylnaphthalen-1-yl)ethanol
[0445] In an analogous procedure to reaction 1i the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
2-methyl-1-naphthylmagnesium bromide to give Examples 84 (15 mg,
25%, isomer A, faster eluent on silica gel column) and 85 (15 mg,
25%, isomer B, slower eluent). MS found: (M+H).sup.+=427.
Examples 86 and 87
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-m-
ethoxynaphthalen-1-yl)ethanol
[0446] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
2-methoxy-1-naphthylmagnesium bromide to give Examples 86 (12 mg,
19%, isomer A, faster eluent on chiral OD column) and 87 (12 mg,
19%, isomer B, slower eluent). MS found: (M+H).sup.+=443.
Examples 88 and 89
1-(2,6-dimethoxyphenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-
-1H-indazol-5-yl)ethanol
[0447] In an analogous procedure to Example 71 and 72, the
homochiral aldehyde from reaction 1h (40 mg, 0.141 mmol) was
reacted with 2,6-dimethoxy-phenyllithium to give Examples 88 (3 mg,
5%, isomer A, faster eluent on chiral AD column) and 89 (4 mg, 7%,
isomer B, slower eluent). MS found: (M+H).sup.+=423.
Examples 90 and 91
1-cyclopentyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)ethanol
[0448] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
cyclopentylmagnesium bromide to give Examples 90 (13 mg, 26%,
isomer A, faster eluent on chiral AD column) and 91 (13 mg, 26%,
isomer B, slower eluent). MS found: (M+H).sup.+=355.
Examples 92 and 93
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-(-
pyrrolidin-1-ylmethyl)phenyl)ethanol
[0449] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
(2-(1-pyrrolidinylmethyl)phenyl)magnesium bromide to give Examples
92 (9.0 mg, 14%, isomer A, faster eluent on chiral AD column) and
93 (5.0 mg, 8%, isomer B, slower eluent). MS found:
(M+H).sup.+=446.
Examples 94 and 95
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(2-(-
morpholinomethyl)phenyl)ethanol
[0450] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (40 mg, 0.141 mmol) was reacted with
(2-(4-morpholinomethyl)phenyl)magnesium bromide to give Examples 94
(14 mg, 22%, isomer A, faster eluent on chiral AD column) and 95 (8
mg, 12%, isomer B, slower eluent). MS found: (M+H).sup.+=462.
Examples 96 and 97
1-(2-chlorophenyl)-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazol-5-yl)ethanol
[0451] In an analogous procedure to Examples 71 and 72, the
homochiral aldehyde from reaction 1h (40 mg, 0.141 mmol) was
reacted with 2-chloro-1-bromobenzene to give Examples 96 (3.0 mg,
5%, isomer A, faster eluent on chiral AD column) and 97 (6.0 mg,
11%, isomer B, slower eluent). MS found: (M+H).sup.+=397.
Example 98
(5R)-5-(2-(2-chlorophenyl)-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethyl--
4,5-dihydro-1H-indazole
[0452] Using a procedure analogous to Example 35, the alcohol from
Example 96 (6.0 mg, 0.015 mmol) was reacted with iodoethane to give
Example 98 (3.5 mg, 55%). MS found: (M+H).sup.+=425.
Examples 99 and 100
(5R)-5-((1,3-dihydroisobenzofuran-1-yl)methyl)-1-(4-fluorophenyl)-5,6-dime-
thyl-4,5-dihydro-1H-indazole
[0453] (99a) In an analogous procedure to reaction 1i, the
homochiral aldehyde from reaction 1h (80 mg, 0.281 mmol) was
treated with 2-(1,3-dioxan-2-yl)phenylmagnesium bromide to provide
the desired alcohols as mixture of two diastereomers (100 mg, 79%).
MS found: (M+H).sup.+=449.
[0454] (99b) Triethylsilane (0.2 mL) and trifluoroacetic acid (0.2
mL) were added to a solution of the alcohols from reaction 99a (80
mg, 0.241 mmol) in dichloromethane (2 mL) at room temperature.
After 1 h at room temperature, the mixture was concentrated and
purified by silica gel column chromatography (EtOAc-hexane, 0 to
30%) to provide the desired compound as a mixture of two
diastereomers (50 mg), which was separated by chiral AD column
(isocratic, i-PrOH/heptane, 15%) to give Examples 99 (30 mg, 37%,
isomer A, faster eluent) and 100 (15 mg, 19%, isomer B, slower
eluent). MS found: (M+H).sup.+=375.
Examples 101 and 102
2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-(4-m-
ethylthiazol-2-yl)ethanol
[0455] In an analogous procedure to Examples 71 and 72, the
homochiral aldehyde from reaction 1h (60 mg, 0.211 mmol) was
reacted with 4-methylthiazole to give Examples 101 (38 mg, 47%,
isomer A, faster eluent on chiral AD column) and 102 (38 mg, 47%,
isomer B, slower eluent). MS found: (M+H).sup.+=384.
Examples 103
2-(1-ethoxy-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol--
5-yl)ethyl)-4-methylthiazole
[0456] Using a procedure analogous to Example 35, the alcohol from
Example 101 (23.0 mg, 0.060 mmol) was reacted with iodoethane to
give Example 103 (17.0 mg, 69%). MS found: (M+H).sup.+=412.
Example 104
2-(1-ethoxy-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol--
5-yl)ethyl)-4-methylthiazole
[0457] Using a procedure analogous to Example 35, the alcohol from
Example 102 (23.0 mg, 0.060 mmol) was reacted with iodoethane to
give Example 104 (22.0 mg, 89%). MS found: (M+H).sup.+=412.
Examples 105 and 106
1-cyclohexyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-
-5-yl)ethanol
[0458] In an analogous procedure to reaction 1i, the homochiral
aldehyde from reaction 1h (60 mg, 0.211 mmol) was reacted with
cyclohexylmagnesium bromide to give Examples 105 (23 mg, 30%,
isomer A, faster eluent on chiral AD column) and 106 (32 mg, 41%,
isomer B, slower eluent). MS found: (M+H).sup.+=369.
Example 107
(5R)-5-(2-cyclohexyl-2-ethoxyethyl)-(-(4-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole
[0459] Using a procedure analogous to Example 35, the alcohol from
Example 105 (13.0 mg, 0.033 mmol) was reacted with iodoethane to
give Example 107 (4.0 mg, 30%). MS found: (M+H).sup.+=397.
Example 108
(5R)-5-(2-cyclohexyl-2-ethoxyethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole
[0460] Using a procedure analogous to Example 35, the alcohol from
Example 106 (18.0 mg, 0.049 mmol) was reacted with iodoethane to
give Example 108 (4.0 mg, 20%). MS found: (M+H).sup.+=397.
Example 109
(R)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-phen-
ylpentan-2-ol
[0461] Using a procedure analogous to reaction 1i, the ketone from
Example 24 (70.0 mg, 0.194 mmol) was reacted with n-propylmagnesium
bromide to give Example 109 as a 3:2 mixture of two diastereomers
(30.0 mg, 38%). MS found: (M+H).sup.+=405.
Example 110
(R)-2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-phen-
ylethanamine
[0462] (110a) A benzene (10 mL) solution of Example 24 (82 mg,
0.228 mmol) and O-benzylhydroxylamine (500 .mu.L, 8 eq) was heated
to reflux for 22 h, concentrated and purified by flash column
chromatography (0-20% EtOAc-hexanes) to give the desired oxime (80
mg, 75%). MS found: (M+H).sup.+=466.
[0463] (110b) To a formic acid (16 mL) solution of the oxime (75
mg, 0.161 mmol) from reaction 110a was added zinc powder (1 g, 96
eq). The resulting suspension was heated to reflux for 1 h, cooled
to room temperature, diluted with EtOAc and filtered through
celite. The filtrate was concentrated and purified by reverse-phase
preparative HPLC (50-90% solvent B gradient) to give Example 110
(73.9 mg, 97%). MS found: (M+H).sup.+=362.
Example 111
(R)-N-(2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-p-
henylethyl)acetamide
[0464] A CH.sub.2Cl.sub.2 (0.6 mL) solution of Example 110 (15 mg,
0.032 mmol), acetic anhydride (4.5 .mu.L, 1.5 eq) and TEA (44
.mu.L, 10 eq) was stirred at room temperature for 1 h. The crude
material was purified by flash column chromatography (40-100%
EtOAc-hexanes) to give Example 111 (11.7 mg, 92%). MS found:
(M+H).sup.+=404.
Example 112
(R)-N,N-diethyl-2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol--
5-yl)-1-phenylethanamine
[0465] A ClCH.sub.2CH.sub.2Cl (0.6 mL) solution of Example 110
(22.6 mg, 0.048 mmol), acetal aldehyde (32.5 mg, 15 eq) and
NaBH(OAc).sub.3 (21.9 mg, 2.2 eq) was stirred at room temperature
for 22 h. The crude material was purified by reverse-phase
preparative HPLC (50-90% solvent B gradient) to give Example 112
(3.2 mg, 13%) as a 1:1 mixture of two diastereomers. MS found:
(M+H).sup.+=418.
Examples 113 and 114
N-ethyl-2-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl-
)-1-phenylethanamine
[0466] In the preparation of Example 112, Example 113 was obtained
by preparative chiral HPLC (Chiralpak AD column, 20% iPrOH-heptane)
as the fast diastereomer (2.3 mg, 12%) and Example 114 was obtained
as the slow diastereomer (1.3 mg, 7%). MS found:
(M+H).sup.+=390.
Example 115
2-((5R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-5-yl-
)-1-phenylethanol
[0467] A MeOH (1 mL) solution of Example 1 (100 mg, 0.276 mmol) and
palladium on carbon (24 mg) was hydrogenated using a hydrogen
balloon for 17 h at room temperature. The mixture was filtered,
concentrated and purified by preparative chiral HPLC (Chiralpak AD
column, 20% iPrOH-heptane) to give the fast eluting diastereomer as
Example 115 (18.6 mg, 19%) and a slow eluting diastereomer (54.4
mg, 54%). MS found: (M+H).sup.+=365.
Example 116
(5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5,6,7-te-
trahydro-1H-indazole
[0468] In an analogous procedure to the synthesis of Examples 35,
Example 115 (8 mg, 0.022 mmol) was converted to Example 116 (4 mg,
47%). MS found: (M+H).sup.+=393.
Examples 117 and 118
2-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1-pheny-
lethanol
[0469] (117a) Sodium (2.76 g, 1.2 eq) and ethanol (4 mL) were added
to ethyl 4-oxocyclohexanecarboxylate (17.02 g, 100 mmol) in ethyl
ether (500 mL) at room temperature. After 20 h, water (200 mL) and
1 N HCl (200 mL) were added. The two layers were separated. The
aqueous phase was extracted with ethyl ether (2.times.100 mL). The
combined ether phase was dried (MgSO.sub.4) and concentrated to
give a yellow liquid. The crude ketoaldehyde was taken to next step
without purification.
[0470] (117b) Sodium acetate (9.02 g, 1.1 eq) was added to a
solution of the crude ketoaldehyde from reaction 117a (assumed 100
mmol) and 4-fluorophenylhydrazine hydrochloride (17.89 g, 1.1 eq)
in acetic acid (200 mL) at room temperature. After 4 h at room
temperature, the mixture was concentrated. The residue was
carefully quenched with saturated NaHCO.sub.3 (400 mL) and
extracted with EtOAc-hexane (1:1, 3.times.200 mL). The combined
extracts were washed with water (20 mL), brine (20 mL), dried
(MgSO.sub.4) and concentrated. Silica gel chromatography
(EtOAc-hexane, 0 to 50%,+10% CH.sub.2Cl.sub.2) yielded the desired
ethyl
1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate
(7.37 g, 26% for 2 steps) and the undesired ethyl
2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate
(4.94 g, 17% for 2 steps). MS found: (M+H).sup.+=289.
[0471] (117c) A 2 M solution of LDA (6.98 mL, 1.5 eq, from Aldrich)
was added to the desired product from reaction 117b (2.68 g, 9.30
mmol) in THF (100 mL) at 0 .sup.co. After 1 h at 0 .sup.co,
iodomethane (1.74 mL, 3 eq) was added. After an additional hour at
0 .sup.co, saturated NH.sub.4Cl (100 mL) was added. THF was
evaporated in vacuo. The aqueous residue was extracted with EtOAc
(3.times.100 mL). The extracts were washed with brine (10 mL),
dried (MgSO.sub.4) and concentrated. Silica gel chromatography
(EtOAc-hexane, 5 to 25%) gave the desired methylated product (1.139
g, 41%). MS found: (M+H).sup.+=303.
[0472] (117d) A 1.5 M toluene solution of DIBAL (4.46 mL, 1.8 eq)
was added over 15 min to a solution of the ester from reaction 117c
(1.124 g, 3.72 mmol) in CH.sub.2Cl.sub.2 (50 mL) at -78.degree. C.
After 0.5 h at -78.degree. C., the cold bath was removed and the
mixture was immediately quenched with saturated Rochelle salt (100
mL). The mixture was stirred vigorously for 2 h and the two phases
were separated. The aqueous phase was extracted with
CH.sub.2Cl.sub.2 (2.times.50 mL). The combined organic phase was
dried (MgSO.sub.4) and concentrated. Silica gel chromatography
(EtOAc-hexane, 10 to 50%) gave the desired aldehyde (356.6 mg, 37%)
and over-reduced alcohol (485.2 mg, 50%). MS found:
(M+H).sup.+=259.
[0473] (117e-g) Following conditions for reactions 1g-i, the
aldehyde from reaction 117d was homologated and reacted with
phenylmagnesium bromide. Silica gel chromatography (EtOAc-hexane,
10 to 30%) gave Example 117 as the fast eluting isomer (178 mg, 37%
for 3 steps) and Example 118 as the slow eluting isomer (167.2 mg,
37% for 3 steps). MS found: (M+H).sup.+=335 1.
Examples 119 and 120
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro--
1H-indazole
[0474] Using a procedure analogous to Example 35, the alcohols from
Examples 117 and 118 were reacted with iodoethane to give Examples
119 and 120, respectively. MS found: (M+H).sup.+=379.
Examples 121 and 122
2-(1-(4-fluorophenyl)-5-methyl-6-(trifluoromethyl)-4,5-dihydro-1H-indazol--
5-yl)-1-phenylethanol
[0475] (121a) 60% sodium hydride in mineral oil (105 mg, 0.05 eq)
was added the solution of ethyl
4,4,4-trifluoro-2-methyl-3-oxobutanoate (10.39 g, 52.5 mmol) in
benzene (50 mL) at room temperature. After 10 min, methyl vinyl
ketone (4.73 mL, 1.1 eq) was added. The mixture was stirred for 4 h
and filtered through a silica gel pad. The pad was rinsed with
EtOAc until free of product. The filtrate was concentrated to give
a colorless liquid (14.4 g, 96%). MS found: (M+H).sup.+=269.
[0476] (121b) p-Toluenesulfonic acid monohydrate (999 mg, 0.1 eq)
was added to the crude material from reaction 121a (assumed 52.5
mmol) in benzene (200 mL). The mixture was heated to reflux for 2 h
while a Dean-Stark trap was used to azeotropically remove water.
Additional TsOH (1.98 g, 0.2 eq) was added. After 15 h at reflux,
another batch of TsOH (4.95 g, 0.5 eq) was added. After another 5 h
of reflux, the mixture was filtered through a silica gel pad. The
pad was rinsed with EtOAc-hexane (1:1) until free of product. The
filtrate was concentrated to give a mixture of the desired
cyclohexenone product and unreacted starting material. Silica gel
chromatography (EtOAc-hexane, 5 to 15%) yielded the desired
cyclohexenone (4.69 g, 36% for 2 steps). MS found:
(M+H).sup.+=251.
[0477] (121c) The cyclohexenone from reaction 121b (3.94 g, 15.8
mmol) in N,N-dimethylformamide dimethyl acetal (50 mL) was stirred
at 110.degree. C. for 15 h, and concentrated to give a brown solid.
The crude enamine was taken to next step without purification. MS
found: (M+H).sup.+=306.
[0478] (121d-h) Following conditions for reactions 1e-i, the
enamine from reaction 121c was reacted with 4-fluorophenylhydrazine
hydrochloride, reduced to aldehyde, homologated and reacted with
phenylmagnesium bromide. Reverse phase HPLC (75 to 100% solvent B
gradient) gave Example 121 as the fast eluting isomer and Example
122 as the slow eluting isomer. MS found: (M+H).sup.+=417.
Example 123
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-6-(trifluoromethyl)-
-4,5-dihydro-1H-indazole
[0479] Using a procedure analogous to Example 35, the alcohol from
Example 122 was reacted with iodoethane to give Example 123. MS
found: (M+H).sup.+=445.
Example 124
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1-
H-indazol-6-yl)methanol
[0480] (124a) Selenium dioxide (62 mg, 2.0 eq) was added to a
solution of the ether from Example 36 (110 mg, 0.282 mmol) in
1,4-dioxane (4 mL) at room temperature. The mixture was heated to
reflux for 3 h, cooled to room temperature and diluted with EtOAc
(100 mL), washed with water (10 mL), brine (10 mL), dried
(MgSO.sub.4) and concentrated. Silica gel chromatography
(EtOAc-hexane, 0 to 50%) yielded the desired aldehyde (100 mg,
88%). MS found: (M+H).sup.+=405.
[0481] (124b) Sodium borohydride (14 mg, 3.0 eq) was added to a
solution of the aldehyde from reaction 124a (50 mg, 0.124 mmol) in
MeOH (1 mL). After 0.5 h at room temperature, the mixture was
quenched with water (1 mL), diluted with EtOAc (60 mL), washed with
water (5 mL), brine (5 mL), dried (MgSO.sub.4) and concentrated.
Silica gel chromatography (EtOAc-hexane, 0 to 50%) yielded Example
124 (32 mg, 64%). MS found: (M+H).sup.+=407.
Example 125
(5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-5-met-
hyl-4,5-dihydro-1H-indazole
[0482] Using a procedure analogous to Example 35, the alcohol from
Example 124 (15.0 mg, 0.037 mmol) was converted to Example 125 (5.0
mg, 32%). MS found: (M+H).sup.+=421.
Example 126
((5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1-
H-indazol-6-yl)methyl pivalate
[0483] Triethylamine (37.5 mg, 5.0 eq) and pivaloyl chloride (17.9
mg, 2.0 eq) were added to a solution of the alcohol from Example
124 (30 mg, 0.074 mmol) in CH.sub.2Cl.sub.2 (2 mL). After 24 h at
room temperature, the mixture was quenched with water (1 mL),
diluted with EtOAc (60 mL), washed with water (5 mL), brine (5 mL),
dried (MgSO.sub.4) and concentrated. Silica gel chromatography
(EtOAc-hexane, 0 to 50%) yielded Example 126 (30 mg, 82%). MS
found: (M+H).sup.+=491.
Example 127
(5R)-5-(2-ethoxy-2-phenylethyl)-6-ethyl-1-(4-fluorophenyl)-5-methyl-4,5-di-
hydro-1H-indazole
[0484] A 3.0 M solution of methylmagnesium bromide (0.08 mL, 6.0
eq) and copper(I) chloride (2.0 mg, 0.6 eq) were added to a
solution of the ester from Example 126 (20 mg, 0.041 mmol) in
diethyl ether (2 mL) at -20.degree. C. After 0.5 h at 0.degree. C.,
the mixture was quenched with water (1 mL), diluted with EtOAc (60
mL), washed with water (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. Silica gel chromatography (EtOAc-hexane, 0 to 50%)
yielded Example 127 (10 mg, 60%). MS found: (M+H).sup.+=405.
Example 128
(5R)-6-(difluoromethyl)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-me-
thyl-4,5-dihydro-1H-indazole
[0485] A solution of DAST (12.0 mg, 1.5 eq) in CH.sub.2Cl.sub.2
(0.5 mL) was added to a solution of the aldehyde from reaction
124(a) (20 mg, 0.05 mmol) in CH.sub.2Cl.sub.2 (1 mL) at -78.degree.
C. After stirring at room temperature for 24 h, the mixture was
quenched with water (1 mL), diluted with EtOAc (60 mL), washed with
water (5 mL), brine (5 mL), dried (MgSO.sub.4) and concentrated.
Silica gel chromatography (EtOAc-hexane, 0 to 20%) yielded Example
128 (3.0 mg, 14%). MS found: (M+H).sup.+=427.
Example 129
2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-1-phenylethano-
l
[0486] (129a) 60% sodium hydride in mineral oil (150 mg, 0.05 eq)
was added to a solution of 2-formylpropionic acid ethyl ester (9.75
g, 75.0 mmol) and methyl vinyl ketone (5.76 g, 1.1 eq) in benzene
(150 mL) at room temperature. After 24 h at room temperature, the
mixture was quenched with acetic acid (0.4 mL) and filtered through
a silica gel pad. The pad was washed with diethyl ether until free
of product. The filtrate was concentrated to yield the desired
compound (14.4 g, 96%).
[0487] (129b) Acetic acid (4.11 g, 0.95 eq) and piperidine (4.90 g,
0.8 eq) were added to a solution of the compound from reaction 129a
(14.4 g, 72.0 mmol) in THF (100 mL) at room temperature. The
mixture was heated to reflux for 24 h, cooled to room temperature
and filtered through a silica gel pad. The pad was washed with
diethyl ether until free of product. The filtrate was concentrated
and purified by silica gel chromatography (EtOAc-hexane, 0 to 50%)
to yield the desired cyclic ketone (9.25 g, 71%). MS found:
(M+H).sup.+=183.
[0488] (129c-g) Using procedures analogous to reactions 1d-h the
cyclic ketone from reaction 129b (11.4 g, 62.6 mmol) was converted
to the desired aldehyde as a racemic material (5.87 g, 35% for 5
steps). MS found: (M+H).sup.+=271.
[0489] (129h) Using a procedure analogous to reaction 1i, the
aldehyde from reaction 129g (200 mg, 0.741 mmol) was converted to
Example 129 as a 1:1:1:1 mixture of four isomers (250 mg, 96%). MS
found: (M+H).sup.+=349.
Example 130
2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-1-phenylethano-
l
[0490] (130a) The racemic aldehyde from reaction 129g (2.3 g) was
separated by chiral AS column (CO.sub.2/IPA with 0.1% TFA) to
provide enantiomer A (faster eluent, 650 mg, 28%) and enantiomer B
(slower eluent, 650 mg, 28%). MS found: (M+H).sup.+=271.
[0491] (130b) Using a procedure analogous to reaction 1i,
enantiomer B of the aldehyde from reaction 130a (500 mg, 1.85 mmol)
was converted to Example 130 as a 1:1 mixture of two diastereomers
(610 mg, 95%). MS found: (M+H).sup.+=349.
Example 131
2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-1-phenylethano-
l
[0492] Using a procedure analogous to reaction 1i, enantiomer A of
the aldehyde from procedure 130a (500 mg, 1.85 mmol) was converted
to Example 131 as a 1:1 mixture of two diastereomers (610 mg, 95%).
MS found: (M+H).sup.+=349.
Example 132
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-inda-
zole
[0493] Using a procedure analogous to Example 35, the alcohol from
Example 129 (230 mg, 0.663 mmol) was converted to Example 132 as a
1:1:1:1 mixture of four isomers (160 mg, 64%). MS found:
(M+H).sup.+=377.
Example 133
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-inda-
zole
[0494] (133a) The diastereomer mixture of the alcohol from Example
130 (600 mg) was separated by chiral AD column (isocratic,
i-PrOH/heptane, 20%) to give diastereomer A (290 mg, 48%, faster
eluent) and diastereomer B (290 mg, 48%, slower eluent). MS found:
(M+H).sup.+=349.
[0495] (133b) Using a procedure analogous to Example 35,
diastereomer A of the alcohol from reaction 133a (270 mg, 0.776
mmol) was converted to Example 133 (200 mg, 69%). MS found:
(M+H).sup.+=377.
Example 134
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-inda-
zole
[0496] Using a procedure analogous to Example 35, diastereomer B of
the alcohol from reaction 133a (270 mg, 0.776 mmol) was converted
to Example 134 (150 mg, 51%). MS found: (M+H).sup.+=377.
Example 135
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro--
1H-indazol-6-ol
[0497] (135a) 3-chloroperoxybezoic acid (24 mg, 2.0 eq) was added
to a solution of the compound from Example 134 (20 mg, 0.053 mmol)
in CH.sub.2Cl.sub.2 (2 mL) at 0.degree. C. After 2 h to room
temperature, the mixture was carefully quenched with saturated
NaHCO.sub.3 (1 mL) and diluted with EtOAc (80 mL), washed with
water (5 mL), brine (5 mL), dried (MgSO.sub.4) and concentrated.
Silica gel chromatography (EtOAc-hexane, 0 to 30%) yielded the
desired epoxide (16.0 mg, 77%). MS found: (M+H).sup.+=393.
[0498] (135b) A 1.0 M THF solution of lithium aluminum hydride
(0.06 mL, 3.0 eq) was added to a solution of the epoxide from
reaction 135a (8.0 mg, 0.020 mmol) in THF (1 mL) at 0.degree. C.
After stirring at room temperature for 3 h, the mixture was
carefully quenched with EtOAc (60 mL), washed with water (5 mL),
brine (5 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (EtOAc-hexane, 0 to 40%) yielded Example 135 (3.0
mg, 38%, fast eluting isomer) and a slow eluting isomer (3.0 mg,
38%). MS found: (M+H).sup.+=395.
Example 136
5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro--
1H-indazol-6-ol
[0499] Using similar procedures to reaction 135a-b, the compound
from Example 133 (40 mg, 0.106 mmol) was converted to Example 136
as a 1:1 mixture of two isomers (26 mg, 62% for 2 steps). MS found:
(M+H).sup.+=395.
Example 137
(5R)-5-(2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-6-methoxy-5-methyl-4,5--
dihydro-1H-indazole
[0500] (137a) Dess-Martin periodinane (151 mg, 2.0 eq) was added to
a solution of the alcohols from Example 136 (70.0 mg, 0.178 mmol)
in CH.sub.2Cl.sub.2 (5 mL) at room temperature. After 3 h at room
temperature, the mixture was diluted with EtOAc (80 mL), washed
with water (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. Silica gel chromatography (EtOAc-hexane, 0 to 30%)
yielded the desired ketone (60 mg, 86%). MS found:
(M+H).sup.+=393.
[0501] (137b) sodium hydride in mineral oil (3.0 mg, 3.0 eq) was
added to a solution of the ketone from reaction 137a (10 mg, 0.025
mmol) in DMF (1 mL) at room temperature. The mixture was stirred
for 10 min, then cooled to -10.degree. C. Dimethyl sulfate (9.0 mg,
3.0 eq) in DMF (0.2 mL) was added. The resultant mixture was
stirred at 0.degree. C. for 1 h, quenched with saturated
NaHCO.sub.3 (1 mL), diluted with EtOAc (60 mL), washed with water
(5 mL), brine (5 mL), dried (MgSO.sub.4) and concentrated. Silica
gel chromatography (EtOAc-hexane, 0 to 30%) yielded Example 137
(5.0 mg, 49%). MS found: (M+H).sup.+=407.
Example 138
2-(1-(4-fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl-
)-1-phenylethanol
[0502] (138a) A 2 M solution of LDA (6.00 mL, 1.2 eq, from Aldrich)
was added dropwise to the desired product from reaction 117b (2.88
g, 10.0 mmol) in THF (100 mL) at -78 .sup.co. After 1.5 h at -78
.sup.co, allyl bromide (2.54 mL, 3 eq) was added. The mixture was
stirred at -78 .sup.co for 1.5 h and at ambient temperature for 30
min. After addition of saturated NH.sub.4Cl (100 mL), THF was
evaporated in vacuo. The aqueous residue was extracted with EtOAc
(3.times.100 mL). The extracts were dried (MgSO.sub.4) and
concentrated. Silica gel chromatography (EtOAc-hexane, 10 to 25%)
gave the desired product (2.28 g, 70%) as a colorless liquid. MS
found: (M+H).sup.+=329.
[0503] (138b) Ozone was bubbled through a solution of the material
from reaction 138a (2.20 g, 6.70 mmol) in MeOH (50 mL) and
CH.sub.2Cl.sub.2 (50 mL) at -78 .sup.co until the solution turned
yellow. Polystyrene-supported PPh.sub.3 (10.05 g, 1 mmol/g) was
added and the mixture was stirred at ambient temperature for 20 h.
The mixture was concentrated and filtered through a celite pad. The
celite pad was rinsed with EtOAc. The filtrate was concentrated and
purified by silica gel chromatography (EtOAc-hexane, 20 to 50%) to
give the desired aldehyde (1.24 g, 56%). MS found:
(M+MeOH+H).sup.+=363.
[0504] (138c) A 1.0 M THF solution of phenylmagnesium bromide (843
mL, 1.1 eq)) was added dropwise to the aldehyde from reaction 138b
(252.8 mg, 0.766 mmol) in THF (5 mL) at 0 .sup.co. After 1 h, the
mixture was quenched with saturated NH.sub.4Cl (20 mL). THF was
evaporated in vacuo. The aqueous residue was extracted with diluted
with EtOAc (2.times.20 mL). The extracts were dried (MgSO.sub.4)
and concentrated. Silica gel chromatography (EtOAc-hexane, 20 to
40%) followed by reverse phase HPLC (60 to 90% solvent B gradient)
separated two spirolactone isomers: isomer A (47.8 mg, 17%, fast
eluting isomer from RP HPLC), isomer B (63.1 mg, 23%, slow eluting
isomer). MS found: (M+H).sup.+=363.
[0505] (138d) A 1.5 M toluene solution of DIBAL (0.130 mL, 1.5 eq)
was added to isomer B from reaction 138c (47.1 mg, 0.130 mmol) in
CH.sub.2Cl.sub.2 (5 mL) at -78.degree. C. After 0.5 h at
-78.degree. C., additional DIBAL (0.130 mL, 1.5 eq) was added.
After another 30 min, the cold bath was removed and the mixture was
immediately quenched with saturated Rochelle salt (20 mL). The
mixture was stirred overnight and extracted with CH.sub.2Cl.sub.2
(3.times.10 mL). The combined extracts were dried (MgSO.sub.4) and
concentrated. Silica gel chromatography (EtOAc-hexane, 20 to 40%)
gave the desired lactol (41.6 mg, 88%). MS found:
(M+H).sup.+=365.
[0506] (138e) Lithium aluminum hydride (100 mg) was added to the
lactol from reaction 138d (19.1 mg, 0.0525 mmol) in THF. After 1 h
at room temperature, the mixture was quenched with saturated
NH.sub.4Cl (15 mL) and extracted with EtOAc (3.times.10 mL). The
combined extracts were dried (MgSO.sub.4) and concentrated. Silica
gel chromatography (EtOAc-hexane, 30 to 80%) gave Example 138 (14.0
mg, 73%). MS found: (M+H).sup.+=367.
Example 139
(R)-N-(2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)ethy-
l)-1,3,4-thiadiazol-2-amine
[0507] Titanium(IV) isopropoxide (32.8 mg, 1.1 eq) and sodium
triacetoxyborohydride (67 mg, 3.0 eq) were added to a mixture of
the homochiral aldehyde from reaction 1h (30 mg, 0.105 mmol) and
2-amino-1,3,4-thiadiazole (21 mg, 2.0 eq) in 1,2-dichloroethane (2
mL) at room temperature. After 2 h at 80.degree. C., the mixture
was cooled to room temperature and saturated NaHCO.sub.3 (2 mL) and
EtOAc (60 mL) were added. The mixture was washed with water (5 mL),
brine (5 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (EtOAc-hexane, 80 to 100%) yielded Example 139 (18.0
mg, 46%). MS found: (M+H).sup.+=370.
Example 140
(R)-5-(2-(benzyloxy)ethyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H--
indazole
[0508] Using a procedure analogous to Example 35, the alcohol from
Example 23 (20 mg, 0.070 mmol) was reacted with benzyl bromide to
give Example 140 (10.0 mg, 38%). MS found: (M+H).sup.+=377.
Example 141
(R)-N-benzyl-2-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1-indazol-5-yl-
)ethanamine
[0509] Sodium triacetoxyborohydride (45 mg, 3.0 eq) was added to a
mixture of the homochiral aldehyde from reaction 1h (20 mg, 0.704
mmol) and benzylamine (16 mg, 2.0 eq) in 1,2-dichloroethane (2 mL).
After 24 h at room temperature, the mixture was quenched with
saturated NaHCO.sub.3 (2 mL). Following addition of EtOAc (60 mL),
the mixture was washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. Reverse phase HPLC purification
(methanol-water, 20 to 100%) yielded Example 141 as a TFA salt (9.0
mg, 27%). MS found: (M+H).sup.+=376.
Example 142
(S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-phenylallyl)-4,5-dihydro-1H-indaz-
ole
[0510] To a toluene (1.5 mL) solution of Example 24 (40.5 mg, 0.11
mmol), THF (50 .mu.L) and pyridine (500 .mu.L) was added Tebbe's
reagent (0.5 M toluene solution, 0.35 mL, 1.6 eq) at -40.degree. C.
The mixture was allowed to warm to room temperature in 2 h then
quenched by adding 1 N NaOH at -10.degree. C. The mixture was
diluted with ether (10 mL), EtOAc (10 mL) and water (10 mL) then
filtered. The organic phase of the filtrate was washed with brine,
dried (MgSO.sub.4) and concentrated. The residue was purified by
silica gel chromatography (0-20% EtOAc-hexanes) to give Example 142
(16.8 mg, 42%). MS found: (M+H).sup.+=359.
Example 143
(R,E)-1-(4-fluorophenyl)-5,6-dimethyl-5-(2-(naphthalen-1-yl)vinyl)-4,5-dih-
ydro-1H-indazole
[0511] p-Toluenesulfonic acid monohydrate (2 mg) was added to a
solution of the alcohol mixture from Examples 11 and 12 (10 mg,
0.0243 mmol) in benzene (5 mL) at room temperature. After 1 h at
reflux, the mixture was cooled to room temperature and
concentrated. Silica gel chromatography (EtOAc-hexane, 0 to 30%)
yielded Example 143 (8.0 mg, 84%). MS found: (M+H).sup.+=395.
Example 144
(R)-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)(phen-
yl)methanol
[0512] (144a) Methyl iodide (6.86 mL, 1.1 eq) and K.sub.2CO.sub.3
(17.97 g, 1.3 eq) were added to an acetone (400 mL) solution of
tert-butyl 3-oxobutanoate (15.82 g, 100 mmol) at room temperature.
After 15 h, the mixture was filtered and the filtrate was
concentrated. The residue was dissolved in ethyl acetate (300 mL),
washed with water (30 mL) and brine (300 mL), dried (MgSO.sub.4)
and concentrated. The crude residue was purified by silica gel
chromatography (5-10% EtOAc-hexanes) to give tert-butyl
2-methyl-3-oxobutanoate as a colorless oil (9.56 g, 56%). MS found:
(M+Na).sup.+=195.
[0513] (144b) A benzene (100 mL) suspension of (S)--BINAP (4.58 g,
1.02 eq) was added to a benzene (100 mL) solution of
bis(acetonitrile)dichloropalladium(II) (1.86 g, 7.2 mmol) at room
temperature. The mixture was stirred for 2 h. The yellow solid was
collected by filtration to give PdCl.sub.2[(S)--BINAP] (5.78 g,
100%).
[0514] (144c) Silver triflate (3.68 g, 2 eq) was added to a water
(1 mL) and acetone (200 mL) solution of PdCl.sub.2[(S)--BINAP]
(5.72 g, 7.15 mmol) from 144b at room temperature. The mixture was
stirred for 5 h then filtered through celite. The filtrate was
concentrated. The residue was dissolved in CH.sub.2Cl.sub.2 (20 mL)
and ether (20 mL). A yellow solid was formed after the solution was
stored overnight. The solid was collected by filtration to give the
active catalyst
[Pd((S)--BINAP)(H.sub.2O).sub.2].sup.2+(OTf).sub.2.sup.- (6.84 g,
90%).
[0515] (144d) The Pd catalyst (2.91 g, 0.1 eq) from reaction 144c
was added to a THF (10 mL) solution of tert-butyl
2-methyl-3-oxobutanoate (4.71 g, 27.4 mmol) from 144a at room
temperature. The solution was cooled to 0.degree. C. and methyl
vinyl ketone (6.74 mL, 3 eq) was added dropwise. The mixture was
stirred at 0.degree. C. for 36 h and allowed to slowly warm to room
temperature overnight. The resultant solution was filtered through
a silica gel pad to remove the catalyst. The filter cake was rinsed
with 30% EtOAc-hexanes. The filtrate was concentrated and purified
by silica gel chromatography (5-25% EtOAc-hexanes) to give the
Michael adduct (4.89 g, 74%) as a colorless oil.
[0516] (144e) To a THF (25 mL) solution of the Michael adduct (5.58
g, 23.1 mmol) from reaction 144d was added piperidine (1.83 mL, 0.8
eq) and HOAc (1.26 mL, 0.95 eq). The resultant solution was heated
to reflux for 20 h. The mixture was filtered through a silica gel
pad and the filter cake was rinsed with 30% EtOAc-hexanes. The
filtrate was concentrated and purified by silica gel chromatography
(5-15% EtOAc-hexanes) to give the desired cyclohexenone (4.30 g,
83%) as a colorless oil. Analytical chiral HPLC (Chiralpak AS
column, 5% EtOH-5% MeOH-90% heptane) determined the optical purity
as 87-88% ee. MS found: (M+H).sup.+=225.
[0517] (144f) To a ether (100 mL) solution of the cyclohexenone
(5.58 g, 23.1 mmol) from 144e and ethyl formate (2.07 g, 1.6 eq)
was added sodium (483 mg, 1.2 eq) and ethanol (0.7 mL). The mixture
was stirred at room temperature for 18 h, quenched with water (200
mL) and acidified to pH 2-3 with 1 N HCl. The mixture was extracted
with EtOAc (3.times.50 mL). The extracts were washed with brine,
dried (MgSO.sub.4) and concentrated to give the desired
ketoaldehyde (4.71 g) as a red oil. MS found: (M+H).sup.+=253.
[0518] (144g) To an acetic acid (50 mL) solution of the
ketoaldehyde (4.71 g) from reaction 144f was added
4-fluorophenylhydrazine HCl salt (3.13 g, 1.1 eq) and sodium
acetate (1.58 g, 1.1 eq). The exothermic mixture was stirred at
room temperature for 2 h. The acetic acid was evaporated in vacuo.
The residue was treated with saturated NaHCO.sub.3 (100 mL) and
extracted with EtOAc (3.times.50 mL). The extracts were washed with
brine, dried (MgSO.sub.4), concentrated and purified by silica gel
chromatography (3-15% EtOAc-hexanes) to give the dihydroindazole
tert-butyl ester (5.75 g, 96% for 2 steps) as an orange viscous
oil. MS found: (M+H).sup.+=343.
[0519] (144h) To a THF (100 mL) solution of the ester (8.28 g,
24.18 mmol) from reaction 144g was added LiAlH.sub.4 (3.02 g, 3.3
eq) at 0.degree. C. under N.sub.2. The mixture was allowed to
slowly warm to room temperature and stirred for 5 h. The reaction
was quenched by carefully adding 1 N NaOH (10 mL) dropwise and
diluted with THF (100 mL) and stirred overnight until all the
aluminum salt precipitated out. The resultant mixture was filtered
through a celite pad and the filter cake was rinsed with 50%
EtOAc-CH.sub.2Cl.sub.2. The combined filtrate was concentrated,
dissolved in EtOAc (150 mL), washed with water (10 mL) and brine
(10 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (0-60% EtOAc-hexanes) followed by crystallization in
ether gave the desired dihydroindazole alcohol (4.39 g, 67%) as
white needles. Analytical chiral HPLC (Chiralcel OJ column, 10%
isopropyl alcohol-90% heptane) determined the optical purity as
>99% ee. MS found: (M+H).sup.+=273.
[0520] (144i) To a CH.sub.2Cl.sub.2 (15 mL) solution of the
dihydroindazole alcohol (0.39 g, 1.44 mmol) from reaction 144h was
added Dess-Martin periodinane (674 mg, 1.1 eq) at room temperature.
The mixture was stirred for 1 h then quenched with saturated
NaHCO.sub.3 (10 mL) and saturated NaHSO.sub.3 (10 mL). The
resultant mixture was stirred for 2 h until it became a clear
2-layer solution. The CH.sub.2Cl.sub.2 layer was separated and
washed with saturated NaHCO.sub.3 (10 mL) and brine (10 mL), dried
(MgSO.sub.4) and concentrated. Silica gel chromatography (0-30%
EtOAc-hexanes) gave the desired aldehyde (0.35 g, 90%) as a white
solid. MS found: (M+Na).sup.+=303.
[0521] (144j) Using a procedure analogous to reaction 1i, the
aldehyde (17.6 mg, 0.065 mmol) from 144i was reacted with
phenylmagnesium bromide (5.5 eq) to give Example 144 (15.2 mg,
67%). MS found: (M+H).sup.+=349.
Example 145
(S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-phen-
ylethanol
[0522] Using a procedure analogous to reaction 1i, the aldehyde
(15.2 mg, 0.056 mmol) from reaction 144i was reacted with
benzylmagnesium bromide (5.5 eq) to give Example 145 (14.8 mg,
73%). MS found: (M+H).sup.+=363.
Examples 146 and 147
(R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3--
phenylpropan-1-ol
[0523] Using a procedure analogous to reaction 1, the aldehyde (43
mg, 0.159 mmol) from reaction 144i was reacted with
phenethylmagnesium chloride (2 eq) to give a 2:1 mixture of the
alcohols. The mixture was separated by preparative chiral HPLC
(Chiralpak AD column, 10% iPrOH-Heptane) to give the fast eluting
isomer as Example 146 (10.7 mg, 18%) and slow eluting isomer as
Example 147 (21.8 mg, 36%). MS found: (M+H).sup.+=377.
Example 148
(S)-1-(4-fluorophenyl)-5-((R)-1-methoxy-3-phenylpropyl)-5,6-dimethyl-4,5-d-
ihydro-1H-indazole
[0524] In an analogous procedure to the synthesis of Examples 35,
Example 146 (8.5 mg, 0.023 mmol) was converted to Example 148 (3.8
mg, 43%). MS found: (M+H).sup.+=391.
Example 149
(S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-phen-
ylpropan-1-one
[0525] Using a procedure analogous to reaction 144i, Example 147
was converted to Example 149. MS found: (M+H).sup.+=375.
Examples 150 and 151
(R)-1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3--
methyl-3-phenylbutan-1-ol
[0526] Using a procedure analogous to reaction 1i, the aldehyde
(82.5 mg, 0.306 mmol) from reaction 144i was reacted with
(2-methyl-2-phenylpropyl)magnesium chloride. Silica gel
chromatography (0-30% EtOAc-hexanes) gave Example 150 (45.2 mg,
37%, fast eluting isomer), Example 151 (12.2 mg, 10%, slow eluting
isomer) and a 1:1 mixture of the two isomers (23.6 mg, 19%). MS
found: (M+H).sup.+=405.
Example 152
(S)-1-(4-fluorophenyl)-5-((R)-1-methoxy-3-methyl-3-phenylbutyl)-5,6-dimeth-
yl-4,5-dihydro-1H-indazole
[0527] In an analogous procedure to the synthesis of Examples 35,
Example 151 (10.5 mg, 0.026 mmol) was converted to Example 152 (6
mg, 55%). MS found: (M+H).sup.+=419.
Example 153
(S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-meth-
yl-3-phenylbutan-1-one
[0528] Using a procedure analogous to reaction 144i, the mixture of
Examples 150 and 151 (23.6 mg, 0.0583 mmol) was converted to
Example 153 (0.20.5 mg, 87%). MS found: (M+H).sup.+=403.
Example 154
(S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylthiomethyl)-4,5-dihydro-1H-in-
dazole
[0529] A mixture of the alcohol (106.6 mg, 0.391 mmol) from
reaction 144h diphenyl disulfide (511 mg, 6 eq) and
tributylphosphine (0.771 mL, 8 eq) in THF (6 mL) was heated at
80.degree. C. for 20 h and concentrated. Silica gel chromatography
(5-25% EtOAc-hexanes) gave Example 154 (136.6 mg, 96%). MS found:
(M+H).sup.+=365.
Example 155
(5S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylsulfinylmethyl)-4,5-dihydro--
1H-indazole
Example 156
(S)-1-(4-fluorophenyl)-5,6-dimethyl-5-(phenylsulfonylmethyl)-4,5-dihydro-1-
H-indazole
[0530] Oxone (296 mg, 1.5 eq) was added to the sulfide (116.8 mg,
0.320 mmol) from Example 154 in MeOH (5 mL) and water (5 mL) at
0.degree. C. After 3 h at 0.degree. C., the MeOH was evaporated in
vacuo. The residue was diluted with EtOAc (30 mL), washed with
NaHCO.sub.3 (2.times.5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. Silica gel chromatography (10-50% EtOAc-hexanes) gave
sulfoxide Example 155 (57.8 mg, 48%) and sulfone Example 156 (13.9
mg, 11%). MS found: (M+H).sup.+=381 for sulfoxide, 397 for
sulfone.
Example 157
(S)-1-(4-fluorophenyl)-5,6-dimethyl-N-(2-phenylpropan-2-yl)-4,5-dihydro-1H-
-indazole-5-carboxamide
[0531] (157a) A mixture of the ester from reaction 144g (580.4 mg,
1.70 mmol), trifluoroacetic acid (10 mL) and CH.sub.2Cl.sub.2 (10
mL) was stirred at room temperature for 15 h, then concentrated.
Silica gel chromatography (0-10% MeOH--CH.sub.2Cl.sub.2) gave the
desired acid (573 mg, 100%). MS found: (M+H).sup.+=287.
[0532] (157b) 2-Phenylpropan-2-amine (31.4 mg, 2 eq), HOBt
monohydrate (23.5 mg, 1.5 eq), EDC hydrochloride (40 mg, 1.8 eq)
and Hunig base (0.121 mL, 6 eq) were added to the acid from
reaction 157a (31.9 mg, 0.116 mmol) in CH.sub.3CN (2 mL) at room
temperature. The resultant mixture was stirred at room temperature
for 30 min and at 80.degree. C. for 15 h. Following addition of
EtOAc (30 mL), the mixture was washed with saturated NH.sub.4Cl (5
mL), brine (5 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (10-50% EtOAc-hexanes) gave Example 157 (25.5 mg,
55%). MS found: (M+H).sup.+=404.
Example 158
(S)-benzyl
1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-ylcarb-
amate
[0533] Diphenylphosphoryl azide (669 mg, 1.3 eq) was added to the
acid from reaction 157a (535 mg, 1.87 mmol) and triethylamine (0.65
mL, 2.5 eq) in benzene (20 mL). After 1 h at room temperature,
benzyl alcohol (0.387 mL, 2 eq) was added. The mixture was heated
to reflux for 18 h, then concentrated. Silica gel chromatography
(10-30% EtOAc-hexanes) gave Example 158 (246.6 mg, 34%). MS found:
(M+H).sup.+=392.
Example 159
(S)-allyl
1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-ylcarba-
mate
[0534] In an analogous procedure to the synthesis of Examples 158,
the acid from reaction 157a was reacted with allylic alcohol to
give Example 159. MS found: (M+H).sup.+=342.
Example 160
(S)-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl-
)aniline
[0535] To a CH.sub.2Cl.sub.2 (2 mL) solution of the aldehyde (65.8
mg, 0.24 mmol) from reaction 144i was added aniline (33.3 mg, 1.5
eq) and 4 A molecular sieve (28.5 mg). The mixture was heated at
60.degree. C. for 16 h then cooled to room temperature.
NaBH(OAc).sub.3 (172 mg, 3 eq) was added. The mixture was stirred
at room temperature overnight then purified by silica gel
chromatography (0-20% EtOAc-hexanes) to give Example 160 (83.5 mg,
99%) as a yellow oil. MS found: (M+H).sup.+=348.
Example 161
(S)-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl-
)-N-phenylacetamide
[0536] A CH.sub.2Cl.sub.2 (1 mL) solution of Example 160 (18.6 mg,
0.054 mmol), acetic anhydride (50.6 .mu.L, 10 eq) and triethylamine
(74.6 .mu.L, 10 eq) was stirred at room temperature for 19 h. The
mixture was purified by silica gel chromatography (0-55%
EtOAc-hexanes) to give Example 161 (18.1 mg, 87%). MS found:
(M+H).sup.+=390.
Example 162
(S)-N-ethyl-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-y-
l)methyl)aniline
[0537] To a THF (1 mL) solution of Example 161 (11.5 mg, 0.030
mmol) was added LiAlH.sub.4 (12 mg, 10 eq). The suspension was
stirred at room temperature for 2 h, then quenched by slowly adding
1 N NaOH and diluted with water. The mixture was extracted with
EtOAc. The extract was concentrated and purified by silica gel
chromatography (0-20% EtOAc-hexanes) to give Example 162 (5.6 mg,
50%). MS found: (M+H).sup.+=376.
Example 163
(S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
tert-butylcarbamate
[0538] A ClCH.sub.2CH.sub.2Cl (1 mL) solution of the alcohol (14.7
mg, 0.054 mmol) from reaction 144h, tert-butyl isocyanate (50.8
.mu.L, 8 eq) and triethylamine (76 .mu.L, 10 eq) was heated at
120.degree. C. for 15 h in a sealed tube. The crude material was
purified by reverse-phase HPLC (85-100% solvent B gradient) to give
Example 163 (11.2 mg, 56%). MS found: (M+H).sup.+=372.
Example 164
(S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
phenyl carbonate
[0539] A ClCH.sub.2CH.sub.2Cl (1 mL) solution of the alcohol (16
mg, 0.059 mmol) from reaction 144h, phenyl chloroformate (29.6
.mu.L, 4 eq) and triethylamine (41 .mu.L, 5 eq) was heated at
60.degree. C. for 2 h in a sealed tube. The crude mixture was
purified by reverse-phase HPLC (85-100% solvent B gradient) to give
Example 164 (4.8 mg, 21%). MS found: (M+H).sup.+=393.
Example 165
(S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
phenylcarbamate
[0540] A ClCH.sub.2CH.sub.2Cl (1 mL) solution of the alcohol (13.6
mg, 0.050 mmol) from reaction 144h, phenyl isocyanate (21.9 .mu.L,
4 eq) and triethylamine (35 .mu.L, 5 eq) was heated at 60.degree.
C. for 2 h in a sealed tube. The crude mixture was purified by
reverse-phase HPLC (85-100% solvent B gradient) to give Example 165
(15.5 mg, 79%). MS found: (M+H).sup.+=392.
Example 166
(S)-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)methyl
phenylcarbamate
[0541] (166a) A ClCH.sub.2CH.sub.2Cl (2 mL) solution of the
aldehyde (68 mg, 0.252 mmol) from reaction 144i and
O-benzylhydroxylamine (110.4 mg, 4 eq) was stirred at room
temperature for 4 h. The crude mixture was purified by silica gel
chromatography (0-30% EtOAc-hexanes) to give the oxime (85.3 mg,
91%). MS found: (M+H).sup.+=376.
[0542] (166b) To a formic acid (10 mL) solution of the oxime (85.3
mg, 0.227 mmol) from reaction 166a was added zinc powder (1 g, 68
eq) and the suspension was heated to reflux for 1 h. The mixture
was diluted with EtOAc and filtered through celite. The filtrate
was concentrated. The residue was dissolved in EtOAc, washed with
water and brine, dried (MgSO.sub.4), and concentrated to give the
crude amine (51.3 mg). MS found: (M+H).sup.+=272.
[0543] (166c) A ClCH.sub.2CH.sub.2Cl (1.5 mL) solution of the amine
(11.5 mg) from reaction 166b, phenyl chloroformate (12 .mu.L, 2 eq)
and triethylamine (17.5 PL, 3 eq) was stirred at room temperature
for 19 h. The crude mixture was purified by reverse-phase HPLC
(75-95% solvent B gradient) to give example 166 (5.7 mg, 34%
2-step). MS found: (M+H).sup.+=392.
Example 167
(S)-1-tert-butyl-3-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)methyl)urea
[0544] A ClCH.sub.2CH.sub.2Cl (1.5 mL) solution of the amine (14
mg) from reaction 166b and tert-butyl isocyanate (12 .mu.L, 2 eq)
was stirred at room temperature for 19 h. The crude mixture was
purified by reverse-phase HPLC (75-95% solvent B gradient) to give
example 167 (4.7 mg, 24% 2-step). MS found: (M+H).sup.+=371.
Example 168
(R,E)-1-(4-fluorophenyl)-5,6-dimethyl-5-styryl-4,5-dihydro-1H-indazole
[0545] A 1 M THF solution of NaHMDS (5.59 mL, 3 eq) was added to
diethyl benzylphosphonate (1.48 g, 3.5 eq) in THF (50 mL) at
-78.degree. C. The mixture was stirred at 0.degree. C. for 1 h,
then cooled to -78.degree. C. The aldehyde from reaction 144i (503
mg, 1.86 mmol) in THF (5 ml-L) was added dropwise. The mixture was
stirred at -78.degree. C. for 2 h, and quenched with saturated
NH.sub.4Cl (100 mL). THF was evaporated in vacuo. The residue was
extracted with EtOAc (3.times.100 mL). The extracts were washed
with brine (10 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (0-15% EtOAc-hexanes) gave Example 168 (401.5 mg,
63%). MS found: (M+H).sup.+=345.
Example 169
(S)-5-(1,3-dioxolan-2-yl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-i-
ndazole
[0546] To a CH.sub.2Cl.sub.2 (5 mL) solution of the aldehyde (27.9
mg, 0.103 mmol) from reaction 144i and
bis(O-trimethylsilyl)ethylene glycol (350 .mu.L, 14 eq) was added
TMSOTf (50 .mu.L, 2.7 eq) at room temperature. The mixture was
stirred for 1 h then purified by silica gel chromatography (0-35%
EtOAc-hexanes) to give Example 169 (30.9 mg, 95%). MS found:
(M+H).sup.+=315.
Example 170
(5S)-5-(4H-benzo
[d][1,3]dioxin-2-yl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indaz-
ole
[0547] A ClCH.sub.2CH.sub.2Cl (1 mL) solution of the aldehyde (17.8
mg, 0.066 mmol) from reaction 144i, 2-hydroxylbenzyl alcohol (11.7
mg, 1.4 eq), pTsOH.H.sub.2O (3.4 mg, 0.27 eq) and anhydrous
Na.sub.2SO.sub.4 (69 mg) was heated at 50.degree. C. in a sealed
tube for 24 h. The crude mixture was purified by silica gel
chromatography (0-40% EtOAc-hexanes) to give Example 170 (6.1 mg,
25%). MS found: (M+H).sup.+=377.
Example 171
(S)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-N-(1,3-
,4-thiadiazol-2-yl)propanamide
[0548] (171a) A mixture of the aldehyde 144i (109 mg, 0.40 mmol)
and methyl (triphenylphosphoranylidene)acetate (337 mg, 1.00 mmol)
in acetonitrile (3.3 mL) was heated at 80.degree. C. for 24 h. The
reaction mixture was concentrated under reduced pressure and
purified by flash column chromatography (silica, 20% ethyl acetate
in hexanes) to provide the intermediate alpha, beta unsaturated
ester as an oil (108 mg, 83%). MS found: (M+H).sup.+=327. 1H NMR
(400 MHz, chloroform-D) .delta. ppm 1.27 (s, 3H) 1.81 (s, 3H) 2.69
(d, J=16.00 Hz, 1H) 2.80 (d, J=16.00 Hz, 1H) 3.70 (s, 2H) 5.80 (d,
J=15.77 Hz, 1H) 6.32 (s, 1H) 6.89 (d, J=15.77 Hz, 1H) 7.12-7.19 (m,
2H) 7.39 (s, 1H) 7.44 (dd, J=9.16, 5.09 Hz, 1H).
[0549] (171b) To a solution of the product of reaction 171a (108
mg, 0.33 mmol) in anhydrous methanol was added magnesium turnings
(81 mg, 3.30 mmol) which had previously been dried at 120.degree.
C. overnight under vacuum. The mixture was stirred under nitrogen
for 2.5 h, gradually giving a nearly homogenous solution. 3N
aqueous HCl (8 mL) was then added dropwise to the reaction mixture,
initially giving a gelatinous mixture which gradually became a
free-flowing solution upon agitation, which was partitioned between
ethyl acetate and water. The organic layer was washed sequentially
with saturated aqueous sodium bicarbonate and brine, dried over
sodium sulfate, and concentrated. Purification of the residue by
flash column chromatography (silica, 20% ethyl acetate in hexanes
to 50% ethyl acetate in hexanes) provided the ester as an oil (68
mg, 63%). MS found: (M+H).sup.+=329. 1H NMR (400 MHz, CHLOROFORM-D)
.delta. ppm 1.10 (s, 3H) 1.67-1.83 (m, 2H) 1.86 (s, 3H) 2.19-2.37
(m, 2H) 2.54 (d, J=16.00 Hz, 1H) 2.66 (d, J=16.00 Hz, 1H) 3.62 (s,
3H) 6.23 (s, 1H) 7.14 (t, J=8.39 Hz, 2H) 7.37 (s, 1H) 7.39-7.49 (m,
2H)
[0550] (171c) A cloudy mixture of the product of reaction 171b (68
mg, 0.21 mmol) in THF (4 mL) and 1N aqueous lithium hydroxide (2.07
mL) was stirred at room temperature for 16 h. The reaction mixture
was partitioned between ethyl acetate and 1N aqueous HCl. The
organic layer was dried over sodium sulfate and concentrate to give
the carboxylic acid as an oil (64 mg, 99%). MS found:
(M+H).sup.+=315
[0551] (171d) To a solution of the product of reaction 171c (64 mg,
0.20 mmol) in acetonitrile (2 mL) were sequentially added
triethylamine (0.112 mL, 0.80 mmol), HATU (93 mg, 0.24 mmol), and
2-amino-1,3,4-thiadiazole (40 mg, 0.40 mmol). The mixture was
heated at 45.degree. C. for 3 h, then partitioned between ethyl
acetate and 1N HCl. The organic layer was washed with saturated
aqueous sodium bicarbonate and brine, dried over sodium sulfate,
and concentrate. Purification by flash column chromatography
(silica, 90% ethyl acetate in hexanes to 100% ethyl acetate)
provided the title compound as a white solid (68 mg, 86%). MS
found: (M+H).sup.+=398. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.20 (s, 3H) 1.85-1.98 (m, 5H) 2.54-2.74 (m, 3H) 2.82 (d, J=15.77
Hz, 1H) 6.21 (s, 1H) 7.17 (dd, J=8.39 Hz, 2H) 7.41 (dd, J=8.65,
4.58 Hz, 2H) 7.51 (s, 1H) 8.77 (s, 1H).
Example 172
(S)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-N-(thi-
azol-2-yl)propanamide)
[0552] The title compound was prepared in a manner analogous to the
preparation of the title compound of Example 171, replacing and
2-amino-1,3,4-thiadiazole with 2-aminothiazole. MS found:
(M+H).sup.+=397. 1H NMR (400 MHz, chloroform-D) .delta. ppm 1.20
(s, 3H) 1.79-1.90 (m, 2H) 1.91 (s, 3H) 2.53-2.68 (m, 3H) 2.79 (d,
J=16.00 Hz, 1H) 6.23 (s, 1H) 7.06 (d, J=4.07 Hz, 1H) 7.17 (t,
J=8.65 Hz, 2H) 7.39-7.50 (m, 4H).
Example 173
(S)-N-(4,5-dimethylthiazol-2-yl)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazol-5-yl)propanamide
[0553] The title compound was prepared in a manner analogous to the
preparation of the title compound of Example 171, replacing
2-amino-1,3,4-thiadiazole with 4,5-dimethyl-2-aminothiazole. MS
found: (M+H).sup.+=425. 1H NMR (400 MHz, chloroform-D) .delta. ppm
1.20 (s, 3H) 1.75-1.86 (m, J=8.65, 6.10 Hz, 1H) 1.87-1.97 (m, 1H)
1.91 (s, 3H) 2.29 (s, 6H) 2.50-2.57 (m, 2H) 2.62 (d, J=16.28 Hz,
1H) 2.80 (d, J=16.00 Hz, 1H) 6.20 (s, 1H) 7.19 (t, J=8.65 Hz, 2H)
7.44 (dd, J=9.16, 4.58 Hz, 1H) 7.51 (s, 1H).
Example 174
(S)-3-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-N-(-
1,3,4-thiadiazol-2-yl)propanamide
[0554] (174a) A mixture of the aldehyde of reaction 129e (207 mg,
0.81 mmol) and methyl(triphenylphosphoranylidene)acetate (555 mg,
1.66 mmol) in acetonitrile (7.0 mL) was heated at 80.degree. C. for
22 h. The reaction mixture was concentrated under reduced pressure
and purified by flash column chromatography (silica, 20% ethyl
acetate in hexanes to 30% ethyl acetate in hexanes) to provide the
intermediate alpha, beta unsaturated ester as an oil (234 mg, 93%).
MS found: (M+H).sup.+=313. 1H NMR (400 MHz, chloroform-D) .delta.
ppm 1.27 (s, 3H) 2.72 (d, J=16.00 Hz, 1H) 2.81 (d, J=16.00 Hz, 1H)
3.67 (s, 3H) 5.65 (d, J=9.66 Hz, 1H) 5.81 (d, J=15.77 Hz, 1H) 6.46
(d, J=10.68 Hz, 1H) 6.93 (d, J=15.77 Hz, 1H) 7.12 (t, J=8.00 Hz,
2H) 7.39 (s, 1H) 7.39-7.45 (m, 2H).
[0555] (174b) A solution of the product of reaction 174a (51 mg,
0.16 mmol) in ethyl acetate (2 mL) was treated-with palladium on
carbon catalyst (10% w/w, 5 mg). The atmosphere was exchanged for
hydrogen gas (balloon) and stirred at room temperature for 16 h.
The reaction mixture was purged with nitrogen gas, filtered through
a 0.45 um filter, and concentrated to give the ester as an oil (54
mg, 99%). MS found: (M+H).sup.+=317. 1H NMR (400 MHz, chloroform-D)
.delta. ppm 1.60 (t, J=6.36 Hz, 2H) 1.66-1.74 (m, 2H) 2.29-2.43 (m,
4H) 2.68 (t, J=6.36 Hz, 2H) 3.66 (s, 3H) 7.08-7.15 (m, 2H) 7.41 (s,
1H) 7.46 (dd, J=9.16, 4.58 Hz, 2H).
[0556] (174c) The intermediate carboxylic acid was prepared in a
manner analogous to that described above for the preparation of the
intermediate carboxylic acid 171c of Example 171. MS found:
(M+H).sup.+=313.
[0557] (174d) The title compound was prepared in a manner analogous
to that described above for the preparation of the title compound
of Example 171 from the intermediate 174c. MS found:
(M+H).sup.+=386. 1H NMR (400 MHz, chloroform-D) .delta. ppm 1.07
(s, 3H) 1.70 (t, J=6.36 Hz, 2H) 1.81-1.91 (m, 2H) 2.42 (d, J=16.00
Hz, 1H) 2.51 (d, J=16.00 Hz, 1H) 2.68 (t, J=6.10 Hz, 2H) 2.73-2.86
(m, 2H) 7.08-7.21 (m, 2H) 7.42 (dd, J=9.16, 4.58 Hz, 2H) 7.56 (s,
1H) 8.79 (s, 1H).
Example 175
5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H--
indazole
[0558] (175a) NaH (3.52 g, 3.0 eq) was added to a solution of
(R)-(+)-3-chloro-1-phenyl-1-propanol (5.00 g, 29.3 mmol) and ethyl
iodide (14.6 g, 3.0 eq) in DMF (50 mL) at room temperature. After 1
h at room temperature, the mixture was carefully quenched with
H.sub.2O (10 mL), diluted with EtOAc (400 mL), washed with H.sub.2O
(50 mL), brine (50 mL), dried (MgSO.sub.4) and concentrated. The
crude ether was taken to the step without purification.
[0559] (175b) NaCN (4.31 g, 3.0 eq) was added to a solution of the
crude ether from reaction 175a (6.30 g, 29.3 mmol) in DMSO (30 mL)
at room temperature. The mixture was heated to 60.degree. C. for 6
h then cooled to room temperature. After addition of H.sub.2O (10
mL) and EtOAc (400 mL), the mixture was washed with H.sub.2O (50
mL), brine (50 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (EtOAc-hexane, 0 to 20%) yielded the desired nitrile
(4.95 g, 89% for 2 steps).
[0560] (175c) A 1.6 M solution of n-BuLi in hexane (17.0 mL, 1.05
eq) was added to a solution of N,N-diisopropylamine (2.38 g, 1.1
eq) in THF (80 mL) at -78.degree. C. The mixture was warmed to
0.degree. C. for 0.5 h then cooled to -78.degree. C. A solution of
the nitrile from reaction 175b (4.90 g, 25.9 mmol) in THF (20 mL)
was added over 20 minutes. After 1 h at -78.degree. C., methyl
iodide (4.05 g, 1.1 eq) was added. The mixture was stirred at
0.degree. C. for 1 h, quenched with saturated NaHCO.sub.3 (30 mL)
and diluted with EtOAc (800 mL), washed with water (80 mL), brine
(80 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (EtOAc-hexane, 0 to 20%) gave the desired product
(4.20 g, 80%). MS found: (M+H).sup.+=204.
[0561] (175d) A 1.6 M solution of n-BuLi in hexane (14.1 mL, 1.2
eq) was added to a solution of N,N-diisopropylamine (1.80 g, 1.2
eq) in THF (60 mL) at -78.degree. C. The mixture was stirred at
0.degree. C. for 0.5 h, then cooled to -78.degree. C. A solution of
the nitrile from reaction 175c (3.00 g, 14.8 mmol) in THF (10 mL)
was added over 20 minutes. After 0.5 h at -78.degree. C., HMPA (12
mL, 5 eq) was added. The mixture was stirred at -78.degree. C. for
10 minutes. After addition of 4-bromo-1-butene (2.40 g, 1.2 eq),
the mixture was warmed to 0.degree. C. over 1h, quenched with
saturated NaHCO.sub.3 (30 mL) and diluted with EtOAc (600 mL). The
mixture was washed with water (60 mL), brine (60 mL), dried
(MgSO.sub.4) and concentrated. Silica gel chromatography
(EtOAc-hexane, 0 to 20%) yielded the desired product (3.40 g, 89%).
MS found: (M+H).sup.+=258.
[0562] (175e) A 1.5 M solution of DIBAL in toluene (3.0 mL, 2.0 eq)
was added dropwise to a solution of the product from reaction 175d
(514 mg, 2.00 mmol) in toluene (5 mL) at -78.degree. C. After 1 h
-78.degree. C., methanol (1 mL) and 1N HCl (2 mL) were added. The
mixture was diluted with EtOAc (100 mL), washed with water (5 mL),
saturated NaHCO.sub.3 (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel chromatography
(EtOAc-hexane, 0 to 10%) to yield the desired aldehyde (310 mg,
60%). MS found: (M+Na).sup.+=283.
[0563] (175f) PdCl.sub.2 (20 mg, 0.1 eq) and Cu(OAc).sub.2 were
added to a solution of the aldehyde from reaction 175e (300 mg,
1.15 mmol) in N,N-dimethylacetamide (4.2 mL) and H.sub.2O (0.6 mL).
The mixture was stirred under an oxygen balloon for 24 h, diluted
with EtOAc (100 mL), washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by silica
gel chromatography (EtOAc-hexane, 0 to 30%) to yield the desired
ketone (212 mg, 67%). MS found: (M+Na).sup.+=299.
[0564] (175g) Using conditions analogous to reaction 1c, the ketone
from reaction 175f (6.30 g, 22.8 mmol) was converted to the desired
cyclic ketone as a 2:1 mixture of two diastereomers (4.80 g, 82%).
Separation by chiral AS column (isocratic, i-PrOH/CO.sub.2, 10/90)
gave the major diastereomer A (2.40 g, faster eluent) and the minor
diastereomer B (1.10 g, slower eluent). MS found:
(M+Na).sup.+=281.
[0565] (175h) In analogous procedures to reactions 1d-1e, the major
diastereomer A from reaction 175g (2.40 g, 9.30 mmol) was converted
to Example 175 (2.95 g, 84% for 2 steps). MS found:
(M+H).sup.+=377.
Example 176
5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-6-((trimethylsi-
lyl)ethynyl)-4,5-dihydro-1H-indazole
[0566] (176a) Using similar procedures to reaction 135a-b, the
compound from Example 175 (1.00 g, 2.66 mmol) was converted to the
desired alcohol as a 1:1 mixture of two isomers (870 mg, 83% for 2
steps). MS found: (M+H).sup.+=395.
[0567] (175b) Using a procedure analogous to reaction 137a the
alcohol from reaction 176a (870 mg, 2.21 mmol) was converted to the
desired ketone (600 mg, 69%). MS found: (M+H).sup.+=393.
[0568] (176c) NaH (24 mg, 3.0 eq, 60% in mineral oil) was added to
a solution of the ketone from reaction 176b (78 mg, 0.200 mmol) in
DMF (3 mL) at room temperature. After stirring for 10 minutes, the
mixture was cooled to 0.degree. C. A solution of
N-phenyltrifluoromethanesulfonimide (78 mg, 1.1 eq) in DMF (1 mL)
was added. The resultant mixture was stirred at 0.degree. C. for
0.5 h, quenched with saturated NaHCO.sub.3 (2 mL), diluted with
EtOAc (80 mL), washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by silica
gel chromatography (EtOAc-hexane, 0 to 30%) to yield the desired
triflate (80 mg, 75%). MS found: (M+H).sup.+=525.
[0569] (176d) Copper (I) Iodide (2 mg, 0.1 eq),
(trimethylsilyl)acetylene (10 mg, 1.4 eq) and
dichlorobis(triphenylphosphine) palladium (11) (5 mg, 0.1 eq) were
added to a solution of the triflate from reaction 176c (38 mg,
0.073 mmol) and triethylamine (22 mg, 3.0 eq) in THF (3 mL) at room
temperature. The mixture was stirred under N.sub.2 for 2 h,
quenched with saturated NaHCO.sub.3 (2 mL), diluted with EtOAc (80
mL), washed with water (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel chromatography
(EtOAc-hexane, 0 to 20%) to yield Example 176 (24 mg, 70%). MS
found: (M+H).sup.+=473.
Example 177
5-((R)-2-ethoxy-2-phenylethyl)-6-ethynyl-1-(4-fluorophenyl)-5-methyl-4,5-d-
ihydro-1H-indazole
[0570] A 1.0 M solution of tetrabutylammonium fluoride in THF
(0.085 mL, 2.0 eq) was added to a solution of Example 176 (20 mg,
0.042 mmol) in THF (1 mL) at 0.degree. C. The mixture was stirred
for 1 h, quenched with saturated NaHCO.sub.3 (2 mL), diluted with
EtOAc (80 mL), washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by silica
gel chromatography (EtOAc-hexane, 0 to 20%) to yield Example 177
(13 mg, 77%). MS found: (M+H).sup.+=401.
Example 178
5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-6-phenyl-4,5-di-
hydro-1H-indazole
[0571] A 0.5 M solution of phenylzinc bromide in THF (0.23 mL, 3.0
eq) and tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.2 eq)
were added to a solution of the triflate from reaction 176c (20 mg,
0.038 mmol) in THF (2 mL). The mixture was heated to reflux for 4
h, cooled to room temperature and quenched with saturated
NH.sub.4Cl (1 mL). After addition of EtOAc (60 mL), the mixture was
washed with water (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel chromatography
(EtOAc-hexane, 0 to 30%) to yield Example 178 (12 mg, 70%). MS
found: (M+H).sup.+=453.
Example 179
5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H--
indazole-6-carbonitrile
[0572] Bis(dibenzylideneacetone)palladium (13 mg, 0.3 eq),
diphenylphosphinoferrocene (25 mg, 0.6 eq), zinc (20 mg, 4.0 eq)
and zinc cyanide (89 mg, 10 eq) were added to a solution of the
triflate from reaction 176c (40 mg, 0.076 mmol) in
N,N-dimethylformamide (2 mL). The mixture was heated to 100.degree.
C. under nitrogen for 2 h, cooled to room temperature and quenched
with saturated NaHCO.sub.3 (2 mL). After addition of EtOAc (80 mL),
the mixture was washed with water (5 mL), brine (5 mL), dried
(MgSO.sub.4) and concentrated. The residue was purified by silica
gel chromatography (EtOAc-hexane, 0 to 30%) to yield Example 179
(10 mg, 33%). MS found: (M+H).sup.+=402.
Example 180
6-chloro-5-((R)-2-ethoxy-2-phenylethyl)-1-(4-fluorophenyl)-5-methyl-4,5-di-
hydro-1H-indazole
[0573] (180a) Lithium carbonate (12.7 mg, 1.0 eq) and lithium
chloride (51 mg, 7.0 eq) were added to a solution of the triflate
from reaction 176c (90 mg, 0.17 mmol) in THF (4 mL). After heating
to reflux for 0.5 h, additional hexamethylditin (56 mg, 1.0 eq) in
THF (2 mL) followed by tetrakis(triphenylphosphine)palladium(0) (40
mg, 0.2 eq) were added. The resultant mixture was kept at reflux
for 3 h, cooled to room temperature and quenched with saturated
NaHCO.sub.3 (4 mL). After addition of EtOAc (80 mL), the mixture
was washed with water (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel chromatography
(EtOAc-hexane, 0 to 30%) to yield the desired tin compound (70 mg,
76%). MS found: (M+H).sup.+=539.
[0574] (180b) Copper(II) chloride (20 mg, 3.0 eq) was added to a
solution of the tin compound from reaction 180a (27 mg, 0.050 mmol)
in THF (2 mL) at 0.degree. C. The mixture was stirred at room
temperature for 4 h and quenched with saturated NaHCO.sub.3 (2 mL).
After addition of EtOAc (80 mL), the mixture was washed with water
(5 mL), brine (5 mL), dried (MgSO.sub.4) and concentrated. The
residue was purified by reverse phase HPLC (methanol/water, 70% to
100%, 30 minutes) to yield Example 180 (8 mg, 39%). MS found:
(M+H).sup.+=411.
Example 181
(S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-phen-
ylethane-1,2-dione
[0575] (181a) A solution of Example 201 (360 mg, 1.00 mmol) in THF
(2 mL) was added to a solution of sodium bis(trimethylsilyl)amide
(1.5 mmol, 1.5 eq) in THF (6 mL) at -78.degree. C. After 0.5 h at
-78.degree. C., a solution of
(1S)-(+)-(10-camphorsulfonyl)oxaziridine (458 mg, 2.0 eq) in THF (2
mL) was added. The mixture was stirred at -78.degree. C. for 1 h
and quenched with saturated NH.sub.4Cl (2 mL). After addition of
EtOAc (200 mL), the mixture was washed with water (20 mL), brine
(20 mL), dried (MgSO.sub.4) and concentrated. The residue was
purified by silica gel chromatography (EtOAc-hexane, 10 to 50%) to
yield the desired alcohol as an 8:1 mixture of two diastereomers
(360 mg, 96%). MS found: (M+H).sup.+=377.
[0576] (181b) Iron(III) perchlorate hydrate (30 mg, 0.25 eq) was
added to a solution of the alcohol from reaction 181a (120 mg, 0.32
mmol) at room temperature. The mixture was heated to 45.degree. C.
for 3 h, cooled to room temperature and concentrated. The residue
was purified by silica gel chromatography (EtOAc-hexane, 0 to 30%)
to yield Example 181 (30 mg, 25%). MS found: (M+H).sup.+=375.
Examples 182 and 183
1-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-hydr-
oxy-2-phenylethanone
[0577] The alcohol mixture from reaction 181a (240 mg, 0.67 mmol)
was purified by chiral OD column (isocratic, iso-propanol/heptane,
15/85) to provide Example 182 (120 mg, faster eluent) and Example
183 (14 mg, slower eluent). MS found: (M+H).sup.+=377.
Examples 184 and 185
2-(benzo[b]thiophen-3-yl)-1-((R)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihyd-
ro-1H-indazol-5-yl)propan-2-ol
[0578] (184a) Using a procedure analogous to reaction 1i, the
enantiomer A of the aldehyde from reaction 1h (60 mg, 0.212 mmol)
was converted to the desired alcohol as a mixture of two
diastereomers (80 mg, 90%). MS found: (M+H).sup.+=419.
[0579] (184b) Using a procedure analogous to reaction 144i the
alcohol from reaction 184a (80 mg, 0.19 mmol) was converted to the
desired ketone (60 mg, 76%). MS found: (M+H).sup.+=417.
[0580] (184c) In an analogous procedure to Examples 25 and 26, the
ketone from reaction 184b (55 mg, 0.132 mmol) was converted to
Examples 184 (10.0 mg, 18%, faster eluent on chiral OD column) and
185 (7.0 mg, 12%, slower eluent). MS found: (M+H).sup.+=433.
Example 186
1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-methyl-3-phe-
nylbutan-1-ol
[0581] A 0.5 M ether solution of 2-methyl-2-phenylpropylmagnesium
chloride (5.16 mL, 10 eq) was added to a solution of the aldehyde
from reaction 129e (66.1 mg, 0.258 mmol) in THF (10 mL). After 30
min at room temperature, the mixture was quenched with saturated
NH.sub.4Cl (10 mL) and water (10 mL). After evaporation of THF in
vacuo, the residue was extracted with CH.sub.2Cl.sub.2 (3.times.10
mL). The combined extracts were dried (MgSO.sub.4) and
concentrated. Silica gel chromatography (EtOAc-hexanes, 10% to 30%
gradient) gave Example 186 (67.4 mg, 67%) as a 5:3 mixture of
isomers. MS found: (M+H).sup.+=391.
Examples 187 and 188
1-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3-methy-
l-3-phenylbutan-1-ol
[0582] Using a procedure analogous to Example 186, the aldehyde
(57.5 mg, 0.223 mmol) from reaction 117d was reacted with
2-methyl-2-phenylpropylmagnesium chloride to give Examples 187
(25.1 mg, 29%, fast eluting isomer from silica gel column) and 188
(17.8 mg, 20%, slow eluting isomer). MS found: (M+H).sup.+=393 for
both isomers.
Examples 189 and 190
1-(1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3-pheny-
lpropan-1-ol
[0583] Using a procedure analogous to Example 186, the aldehyde
(53.1 mg, 0.206 mmol) from reaction 117d was reacted with
phenethylmagnesium chloride to give Examples 189 (35.3 mg, 47%,
fast eluting isomer from silica gel column) and 190 (26.0 mg, 35%,
slow eluting isomer). MS found: (M+H).sup.+=365 for both
isomers.
Example 191
1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenylpropan-
-1-ol
[0584] Using a procedure analogous to Example 186, the aldehyde
(53.5 mg, 0.209 mmol) from reaction 129e was reacted with
phenethylmagnesium chloride to give Example 191 (54.7 mg, 72%) as a
1:1 mixture of isomers. MS found: (M+H).sup.+=363.
Example 192
(R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-phenylbu-
tan-2-ol
[0585] Using a procedure analogous to Example 186, the aldehyde
enantiomer B (22.7 mg, 0.084 mmol) from reaction 130a was reacted
with phenethylmagnesium chloride to give Example 192 (23.8 mg, 75%)
as a 1:1 mixture of isomers. MS found: (M+H).sup.+=377.
Example 193
(R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-methyl-4-
-phenylpentan-2-ol
[0586] Using a procedure analogous to Example 186, the aldehyde
enantiomer B (25.5 mg, 0.084 mmol) from reaction 130a was reacted
with 2-methyl-2-phenylpropylmagnesium chloride to give Example 193
(18.9 mg, 50%) as a 1:1 mixture of isomers. MS found:
(M+H).sup.+=405.
Example 194
(S)-5-((4S,6S)-4,6-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)-5,6-dimeth-
yl-4,5-dihydro-1H-indazole
[0587] (194a) TMSOTf (2.47 mL, 13.59 mmol) was added to a
CH.sub.2Cl.sub.2 (15 mL) solution of pyridine (1.0753 g, 1 eq) at
0.degree. C. under nitrogen atmosphere. The resulting cloudy
mixture was allowed to warm to room temperature and stirred
overnight. The resulting clear solution was concentrated to give
the desired salt as white needle crystal (3.4 g, 83%).
[0588] (194b) To a CH.sub.2Cl.sub.2 (5 mL) solution of
(2S,4S)-(+)-pentanediol (209 mg, 2 mmol) was added the salt (1.90
g, 3.1 eq) from reaction 194a at room temperature. The mixture was
stirred for 19 h, filtered through a short bed of silica gel and
concentrated to give the crude bis(O-trimethylsilyl)ether (0.40 g,
80%).
[0589] (194c) Using a procedure analogous to the preparation of
Example 169, the aldehyde from reaction 144i (23 mg, 0.085 mmol)
was reacted with the bis(O-trimethylsilyl)ether (0.24 g, 11 eq)
from reaction 194b to give the title compound (25 mg, 83%). MS
found: (M+H).sup.+=357.
Example 195
(S)-2,4-difluoro-N-((1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazo-
l-5-yl)methyl)benzamide
[0590] The amine (22 mg, 0.081 mmol) from reaction 166b was mixed
with 2,4-difluorobenzoic acid (17 mg, 1.3 eq), HOBt monohydrate (19
mg, 1.7 eq), EDCI hydrochloride (59 mg, 3.8 eq), DIPEA (100 .mu.L,
7 eq) in MeCN (2 mL). The mixture was heated at 70.degree. C. for
2.5 h, then purified by reverse-phase HPLC (70 to 100% solvent B
gradient) to give the title compound (4.5 mg, 14%). MS found:
(M+H).sup.+=412.
Example 196
(R)-5-((1,3-dioxolan-2-yl)methyl)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihy-
dro-1H-indazole
[0591] Using a procedure analogous to the preparation of Example
169, the aldehyde from reaction 1h (22 mg, 0.077 mmol) was reacted
with bis(O-trimethylsilyl)ethylene glycol (380 .mu.L, 20 eq) to
give the title compound (16.3 mg, 64%). MS found:
(M+H).sup.+=329.
Example 197
(S)-5-((4R,5R)-4,5-dimethyl-1,3-dioxolan-2-yl)-1-(4-fluorophenyl)-5,6-dime-
thyl-4,5-dihydro-1H-indazole
[0592] (197a) Using a procedure analogous to reaction 194b,
(2R,3R)-(-)-2,3-butanediol (94 mg, 1 mmol) was converted to the
bis(O-trimethylsilyl)ether (221 mg, 94%).
[0593] (197b) Using a procedure analogous to the preparation of
Example 169, the aldehyde from reaction 144i (16 mg, 0.059 mmol)
was reacted with the bis(O-trimethylsilyl)ether (120 mg, 13 eq)
from reaction 197a to give the title compound (14.4 mg, 71%). MS
found: (M+H).sup.+=343.
Example 198
(R,E)-3-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-1-ph-
enylprop-2-en-1-one
[0594] To a CH.sub.2Cl.sub.2 (1 mL) solution of the aldehyde from
reaction 144i (65 mg, 0.24 mmol), acetophenone (56.2 mL, 2 eq) and
magnesium iodide (77.5 mg, 1.2 eq) was added piperidine (28.5
.mu.L, 1.2 eq). The mixture was stirred at room temperature for 40
min, filtered and purified by flash column chromatography (12 g
ISCO silica gel cartridge, 0 to 40% EtOAc-hexanes gradient) to give
the title compound (48.7 mg, 55%). MS found: (M+H).sup.+=373.
Examples 199 and 200
3-((S)-1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-3-hydr-
oxy-1-phenylpropan-1-one
[0595] The title compound mixture was isolated as byproducts from
the preparation of Example 198 by flash column chromatography. The
mixture was separated by preparative chiral HPLC (Chiralcel OJ
column, 20.times.500 mm, 20% IPA-heptane, 20 mL/min) to give
Examples 199 (13.6 mg, 15%, fast eluting isomer) and 200 (12.4 mg,
13%, slow eluting isomer). MS found: (M+H).sup.+=391 for both
isomers.
Example 201
(S)-1-(1-(4-fluorophenyl)-5,6-dimethyl-4,5-dihydro-1H-indazol-5-yl)-2-phen-
ylethanone
[0596] A CH.sub.2Cl.sub.2 (8 mL) solution of Example 145 (328.3 mg,
0.906 mmol) was reacted with Dess-Martin Periodinane (469.7 mg, 1.2
eq) at room temperature. After 2 h the reaction was quenched by
adding aqueous NaHSO.sub.3 (1.4 M, 5 mL) and stirred until the
white cloudy suspension became a clear solution. The
CH.sub.2Cl.sub.2 phase was separated, washed with saturated
NaHCO.sub.3 (5 mL) and purified by flash column chromatography (12
g ISCO silica gel cartridge, 0 to 25% EtOAc-hexanes) to give the
title compound (303 mg, 93%). MS found: (M+H).sup.+=361.
Example 202
1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenylpropan-
-1-one
[0597] Using a procedure analogous to the preparation of Example
201, Example 191 (48.5 mg, 0.134 mmol) was oxidized to give the
title compound (45.3 mg, 94%). MS found: (M+H).sup.+=361.
Example 203
2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-phenylbutan--
2-ol
[0598] A 3 M THF solution of methylmagnesium bromide (0.15 mL, 5.4
eq) was added to a THF (1 mL) solution of Example 202 (30 mg, 0.083
mmol) at room temperature. After 2.5 h, the reaction was quenched
with saturated NH.sub.4Cl and extracted with EtOAc. The EtOAc layer
was concentrated and purified by flash column chromatography (4 g
ISCO silica gel cartridge, 0 to 50% EtOAc-hexanes) to give the
title compound (25.7 mg, 82%) as a 1:1 mixture of two isomers. MS
found: (M+H).sup.+=377.
Example 204
1,1,1-trifluoro-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl-
)-4-phenylbutan-2-ol
[0599] To a THF (1 mL) solution of Example 202 (7 mg, 0.019 mmol)
and trifluoromethyl trimethylsilane (28 .mu.L, 6.6 eq) at 0.degree.
C. was added a 1 M THF solution of tetrabutylammonium fluoride (128
.mu.L, 6.7 eq). The mixture was slowly warmed to room temperature
overnight. HPLC showed only about 10% conversion. Additional
trifluoromethyl trimethylsilane (374 .mu.L) was added and the
reaction was completed in 1 h. The mixture was concentrated and
purified by reverse-phase HPLC (80 to 100% solvent B gradient) to
give the title compound (2.4 mg, 29%) as a 1:1 mixture of two
isomers. MS found: (M+H).sup.+=431.
Examples 205 and 206
1-((S)-1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-phenylpr-
opan-1-ol
[0600] The mixture from Example 191 (54.9 mg) was separated by
chiral HPLC (Chiralcel AD column, 50.times.250 mm, 10% IPA-heptane,
35 mL/in) to give Examples 205 (20.4 mg, fast eluting isomer) and
206 (31.8 mg, slow eluting isomer). MS found: (M+H).sup.+=363 for
both isomers.
Example 207
1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-methyl-3-phe-
nylbutan-1-one
[0601] Using conditions analogous to the preparation of Example
201, Example 186 (41 mg, 0.105 mmol) was oxidized to give the title
compound (35.9 mg, 88%). MS found: (M+H).sup.+=389.
Example 208
2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-methyl-4-phe-
nylpentan-2-ol
[0602] Using conditions analogous to the preparation of Example
203, Example 207 (10.8 mg, 0.0277 mmol) was reacted with
methylmagnesium bromide to give the title compound (9 mg, 61%) as a
mixture of two isomers. MS found: (M+H).sup.+=405.
Example 209
3-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-5-methyl-5-phe-
nylhexan-3-ol
[0603] A 1.7 M pentane solution of tert-butyllithium (0.56 1 mL,
0.952 mmol) was added to an ether (5 mL) solution of iodoethane
(66.9 mg, 0.429 mmol) at -78.degree. C. After 40 min at -78.degree.
C., Example 207 (9.7 mg, 0.025 mmol) was added. After 80 min, the
mixture was quenched by adding saturated NH.sub.4Cl (2 mL) and
warmed to room temperature. The aqueous was extracted with ethyl
acetate (5 mL). The combined ethyl acetate phase was concentrated
and purified by flash column chromatography (4 g ISCO silica gel
cartridge, 0 to 20% EtOAc-hexanes) to give the title compound (3.5
mg, 33%). MS found: (M+H).sup.+=419.
Example 210
(S)-1-tert-butyl-3-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5--
yl)methyl)urea
[0604] (210a-b) Following conditions analogous to 166a-b, the
aldehyde from reaction 129e (100 mg, 0.39 mmol) was converted to
the primary amine (97 mg), which was taken to next step without
purification. MS found: (M+H).sup.+=258.
[0605] (210c) Following conditions analogous to the preparation of
Example 167, the amine (10 mg) from reaction 210b was reacted with
tert-butyl isocyanate to give the title compound (6.1 mg, 44%). MS
found: (M+H).sup.+=357.
Example 211
(S)-1-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)-3--
(2-phenylpropan-2-yl)urea
[0606] A THF (0.5 mL) solution of the amine (11 mg, 0.0428 mmol)
from reaction 210b and 1,1'-carbonyldiimidazole (7.3 mg, 1 eq) was
stirred at room temperature for 2 h. Cumyl amine (6.2 mg, 1 eq) was
added. The mixture was heated at 75.degree. C. for 2 h,
concentrated and purified by flash column chromatography (4 g ISCO
silica gel cartridge, 0 to 70% EtOAc-hexanes) to give the title
compound (5.9 mg, 33%). MS found: (M+H).sup.+=419.
Example 212
(S)-N-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)-2--
phenylacetamide
[0607] Using conditions analogous to the preparation of Example
195, the amine (13.8 mg, 0.0536 mmol) from reaction 210b was
coupled with phenylacetic acid to give the title compound (7.8 mg,
39%). MS found: (M+H).sup.+=376.
Example 213
(S)-N-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)methyl)-1--
phenylcyclopropanecarboxamide
[0608] Using conditions analogous to the preparation of Example
195, the amine (14.8 mg, 0.0575 mmol) from reaction 210b was
coupled with 1-phenyl-1-cyclopropane carboxylic acid to give the
title compound (12.1 mg, 52%). MS found: (M+H).sup.+=402.
Example 214
(S)-3-(2,4-difluorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-i-
ndazol-5-yl)propan-1-ol
[0609] (214a) Sodium hydride (60% suspension with mineral oil,
148.7 mg, 3.72 mmol) was washed with hexanes to removed oil. To it
was added DMSO (10 mL) and trimethyloxosulfonium iodide (823 mg,
3.74 mmol) at 0.degree. C. After stirring for 1 h, the aldehyde
(118.6 mg, 0.46 mmol) from reaction 129e in DMSO (2 mL) was added
at room temperature. The mixture was stirred for 1.5 h then
quenched with pH 7 phosphate buffer (20 mL) and extracted with
ether (2.times.50 mL). The combined extracts were washed with brine
(5 mL) and concentrated to give the crude epoxide (109.6 mg, 88%).
MS found: (M+H).sup.+=271.
[0610] (214b) To an ether (0.5 mL) suspension of CuCN (2.7 mg, 0.75
eq) was added a 0.25 M ether solution of
2,4-difluorobenzylmagnesium bromide (0.4 mL, 2.5 eq) at -20.degree.
C. under nitrogen atmosphere. After 5 min stirring, a THF (0.5 mL)
solution of the epoxide (10.8 mg, 0.040 mmol) from reaction 214a
was added at -10.degree. C. The mixture was allowed to slowly warm
to room temperature over 1h then quenched with methanol. After
removal of solvent in vacuo, the residue was treated with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated and
purified by flash column chromatography (4 g ISCO silica gel
cartridge, 0 to 40% EtOAc-hexanes) to give the title compound (7.5
mg, 47%) as a 2:1 mixture of isomers. MS found:
(M+H).sup.+=399.
Example 215
(S)-4-(2,4-difluorophenyl)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-i-
ndazol-5-yl)butan-2-ol
[0611] (215a) Using conditions analogous to the preparation of
Example 201, Example 214 (13.8 mg, 0.0346 mmol) was oxidized to the
ketone (10.2 mg, 74%). MS found: (M+H).sup.+=397.
[0612] (215b) Using conditions analogous to the preparation of
Example 203, the ketone (5.1 mg, 0.0129 mmol) from 215a was reacted
with methylmagnesium bromide to give the title compound (3.3 mg,
62%) as a 1:1 mixture of isomers. MS found: (M+H).sup.+=413.
Example 216
(S)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-(3-metho-
xyphenyl)propan-1-ol
[0613] Using conditions analogous to the reaction 214b, the epoxide
(10.8 mg, 0.040 mmol) from reaction 214a was reacted with
3-methoxybenzylmagnesium chloride to give the title compound (11.4
mg, 73%) as a 2:1 mixture of isomers. MS found:
(M+H).sup.+=393.
Example 217
(S)-3-(4-chlorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indaz-
ol-5-yl)propan-1-ol
[0614] Using conditions analogous to the reaction 214b, the epoxide
(10 mg, 0.037 mmol) from reaction 214a was reacted with
4-chlorobenzylmagnesium chloride to give the title compound (1.9
mg, 13%) as a 2:1 mixture of isomers. MS found: (M+H).sup.+=397,
399.
Example 218
(S)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-(3-metho-
xyphenyl)butan-2-ol
[0615] (218a) Using conditions analogous to the preparation of
Example 201, Example 216 (7.4 mg, 0.0189 mmol) was oxidized to the
ketone (4.7 mg, 64%). MS found: (M+H).sup.+=391.
[0616] (218b) Using conditions analogous to the preparation of
Example 203, the ketone (4.7 mg, 0.012 mmol) from reaction 218a was
reacted with methylmagnesium bromide to give the title compound
(4.2 mg, 88%) as a 1:1 mixture of isomers. MS found:
(M+H).sup.+=407.
Example 219
(R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-2-methyl-4-
-phenylbutan-2-ol
[0617] (219a) Using conditions analogous to the preparation of
Example 201, Example 192 (5.3 mg, 0.014 mmol) was oxidized to the
ketone (2.7 mg, 51%). MS found: (M+H).sup.+=375.
[0618] (219b) Using conditions analogous to the preparation of
Example 203, the ketone (2.7 mg, 0.0072 mmol) from 219a was reacted
with methylmagnesium bromide to give the title compound (2.2 mg,
79%) as a 1:1 mixture of isomers. MS found: (M+H).sup.+=391.
Example 220
(R)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-2,4-dimeth-
yl-4-phenylpentan-2-ol
[0619] (220a) Using conditions analogous to the preparation of
Example 201, Example 193 (3.1 mg, 0.00766 mmol) was oxidized to the
ketone (1.7 mg, 55%). MS found: (M+H).sup.+=403.
[0620] (220b) Using conditions analogous to the preparation of
Example 203, the ketone (1.7 mg, 0.004 mmol) from 220a was reacted
with methylmagnesium bromide to give the title compound (1.7 mg,
94%) as a 1:1 mixture of isomers. MS found: (M+H).sup.+=419.
Example 221
(S)-1-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-3-(4-metho-
xyphenyl)propan-1-ol
[0621] Using conditions analogous to the reaction 214b, the epoxide
(46.7 mg, 0.182 mmol) from reaction 214a was reacted with
4-methoxybenzylmagnesium chloride to give the title compound (56.6
mg, 79%) as a 2:1 mixture of isomers. MS found:
(M+H).sup.+=393.
Example 222
(S)-2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)-4-(4-metho-
xyphenyl)butan-2-ol
[0622] (222a) Using conditions analogous to the preparation of
Example 201, Example 221 (27.1 mg, 0.069 mmol) was oxidized to the
ketone (20.4 mg, 76%). MS found: (M+H).sup.+=391.
[0623] (222b) Using conditions analogous to the preparation of
Example 203, the ketone (10.2 mg, 0.0261 mmol) from 222a was
reacted with methylmagnesium bromide to give the title compound
(6.8 mg, 64%) as a 1:1 mixture of isomers. MS found:
(M+H).sup.+=407.
Example 223
(R)-1-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-3-
-(2-phenylpropan-2-yl)urea
[0624] (223a-b) Using conditions analogous to 166a-b, the aldehyde
from 129w (52.3 mg, 0.194 mmol) was converted to the crude amine
(58.1 mg). MS found: (M+H).sup.+=272.
[0625] (223c) Using conditions analogous to the preparation of
Example 211, the amine (8 mg, 0.0295 mmol) from reaction 223b was
reacted with 1,1'-carbonyldiimidazole and cumyl amine to give the
title compound (4.6 mg, 36%). MS found: (M+H).sup.+=433.
Example 224
(R)-1-tert-butyl-3-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol--
5-yl)ethyl)urea
[0626] Using conditions analogous to the preparation of Example
211, the amine (5.4 mg, 0.0199 mmol) from reaction 223b was reacted
with 1,1'-carbonyldiimidazole and tert-butylamine to give the title
compound (2.6 mg, 35%). MS found: (M+H).sup.+=3371.
Example 225
(R)-N-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-1-
-phenylcyclopropanecarboxamide
[0627] Using conditions analogous to the preparation of Example
195, the amine (5.3 mg, 0.0195 mmol) from reaction 223b was coupled
with 1-phenyl-1-cyclopropane carboxylic acid at room temperature to
give the title compound (2.3 mg, 28%). MS found:
(M+H).sup.+=416.
Example 226
(R)-N-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)th-
iazole-2-carboxamide
[0628] (226a) To an ethanol (3 mL) solution of
thiazole-2-carboxylic acid ethyl ester (213 mg, 1.355 mmol) was
added aqueous KOH (2 M, 3.5 mL). The mixture was stirred at room
temperature for 2 h then concentrated, acidified with aqueous HCl
(2 M, 3 mL). The resulting white needle crystal (43 mg) was
collected from the solution by filtration.
[0629] (226b) Using conditions analogous to the preparation of
Example 195, the amine (6.3 mg, 0.0232 mmol) from reaction 223b was
coupled with the acid (3 mg, I eq) from reaction 226a to give the
title compound (2 mg, 22%). MS found: (M+H).sup.+=383.
Example 227
(R)-N-(2-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)ethyl)-2-
-phenylacetamide
[0630] Using conditions analogous to the preparation of Example
195, the amine (6.5 mg, 0.024 mmol) from reaction 223b was coupled
with phenylacetic acid at room temperature to give the title
compound (2.3 mg, 25%). MS found: (M+H).sup.+=390.
Example 228
(S)-1-benzyl-3-((1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-indazol-5-yl)m-
ethyl)urea
[0631] Using conditions analogous to the preparation of Example
211, the amine (14.5 mg, 0.056 mmol) from reaction 223b was reacted
with 1,1'-carbonyldiimidazole and benzylamine to give the title
compound (7.8 mg, 35%). MS found: (M+H).sup.+=391.
Example 229
(S)-1-(2,4-difluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-4,5-dihydro-1H-i-
ndazol-5-yl)pentan-3-ol
[0632] Using conditions analogous to the preparation of Example
209, the ketone (7 mg, 0.018 mmol) from reaction 215a was converted
to the title compound (1.5 mg, 20%) as a 1:1 mixture of isomers. MS
found: (M+H).sup.+=427.
Example 230
(R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-4,5-dihydro-1H-indazole-1--
carboxamide
[0633] (230a) A 3 M ether solution of methylmagnesium bromide (5.07
mL, 1.3 eq) was added to a solution of the nitrile from reaction
175d (3.00 g, 11.7 mmol) in benzene (100 mL) at room temperature.
The mixture was heated to reflux for 18 h, cooled to room
temperature, and carefully quenched with 1 N HCl (50 mL). After
stirring for 30 min, the mixture was diluted with brine (200 mL)
and extracted with EtOAc (3.times.300 mL). The combined extracts
were washed with saturated NaHCO.sub.3 (10 mL), brine (10 mL),
dried (MgSO.sub.4) and concentrated. HPLC and LCMS analysis
indicated that the desired ketone is the minor product while most
of the material is the imine intermediate. The crude material was
stirred in THF (150 mL) and 2 N HCl (100 mL) at room temperature
for 15 h. The reaction was incomplete. Concentrated HCl (35 mL) was
added. The mixture was stirred at room temperature for 1 h and at
reflux for 1 h, then concentrated in vacuo. The residue was taken
up in EtOAc (300 mL), washed with saturated NaHCO.sub.3 (2.times.10
mL), brine (10 mL), dried (MgSO.sub.4) and concentrated. Silica gel
chromatography (EtOAc-hexanes, 0% to 10% gradient) gave the desired
methyl ketone as a colorless liquid (2.18 g, 68%). MS found:
(M+Na).sup.+=297.
[0634] (230b) To a solution of the ketone (2.15 g, 7.85 mmol) from
reaction 230a in N,N-dimethylacetamide (100 mL) and water (15 mL)
were added PdCl.sub.2 (278 mg, 0.2 eq) and Cu(OAc).sub.2 (695 mg,
0.5 eq). The mixture was stirred under balloon pressure oxygen for
three days, diluted with brine (100 mL) and 1 N HCl (100 mL), and
extracted with EtOAc (4.times.100 mL). The combined extracts were
washed with brine (10 mL), dried (MgSO.sub.4) and concentrated.
Silica gel chromatography (EtOAc-hexanes, 5% to 25% gradient) gave
the desired diketone (2.05 g, 90%). MS found: (M+Na).sup.+=313.
[0635] (230c) Piperidine (1.37 mL, 2 eq) and HOAc (0.797 mL, 2 eq)
were added to a solution of the diketone (2.02 g, 6.97 mmol) from
reaction 230b in THF (20 mL). Upon heating to reflux, the resulting
solid became a homogeneous solution. After 20 h at reflux, the
mixture was filtered through a silica gel pad. The pad was rinsed
with ether. The filtrate was concentrated. Silica gel
chromatography (EtOAc-hexanes, 5% to 25% gradient) separated the
desired cyclohexenone (a mixture of two diastereomers) from
unreacted starting material (592 mg, 29%). The product mixture was
further separated using Sunfire reverse phase HPLC (60% to 90%
solvent B gradient) to give a fast eluting isomer (556.9 mg, 29%)
and a slow eluting isomer (476.2 mg, 25%). MS found:
(M-EtOH+H).sup.+=227 for both isomers. The fast eluting isomer
proved to be the desired
(R)-4-((R)-2-ethoxy-2-phenylethyl)-3,4-dimethylcyclohex-2-enone by
chemical conversion to Example 36.
[0636] (230d) To a solution of the fast eluting isomer (423 mg,
1.56 mmol) from reaction 230c in ether (20 mL) was added ethyl
formate (346 mg, 3 eq), sodium (500 mg, washed with hexane then
ether) and ethanol (0.25 mL). The mixture was stirred for 18 h.
After removing the excess sodium with a tweezers, the mixture was
quenched with 1 N HCl (20 mL), brine (20 mL), and extracted with
ether (3.times.20 mL). The combine extracts were washed with brine
(5 mL), dried (MgSO.sub.4) and filtered through a silica gel pad.
The pad was rinsed with ether. The filtrate was concentrated to
give the desired keto-aldehyde (469 mg, 100%), which exists as a
enol form, as a red liquid.
[0637] (230e) To a solution of the enol (15.1 mg, 0.050 mmol) from
reaction 230d in HOAc (2 mL) were added semicarbizide hydrochloride
(6.8 mg, 1.2 eq) and sodium acetate (5.0 mg, 1.2 eq). The mixture
was stirred at room temperature for 16 h and at 70.degree. C. for 2
h, concentrated and purified by reverse phase HPLC (70% to 100%
solvent B gradient) to give Example 230 as a white solid (3.9 mg,
23%). MS found: (M+H).sup.+=340.
Example 231
(R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-1-phenyl-4,5-dihydro-1H-in-
dazole
[0638] To a solution of the enol (22 mg, 0.073 mmol) from reaction
230d in HOAc (2 mL) was added 2-hydrazinobenzothiazole (9.5 mg, 1.2
eq). The mixture was stirred at room temperature for 7 h,
concentrated and purified by silica gel chromatography
(EtOAc-hexanes, 0% to 15% gradient) to give Example 231 as a yellow
liquid (20.7 mg, 76%). MS found: (M+H).sup.+=373.
Example 232
(R)-5-((R)-2-ethoxy-2-phenylethyl)-1,5,6-trimethyl-4,5-dihydro-1H-indazole
[0639] A 0.06 M HOAc solution of methylhydrazine (1.6 mL, 1.2 eq)
was added to the enol (24.0 mg, 0.08 mmol) from reaction 230d. The
mixture was stirred at room temperature for 16 h, concentrated and
purified by reverse phase HPLC (60% to 100% solvent B gradient) to
give Example 232 as a colorless liquid (15.2 mg, 61%). MS found:
(M+H).sup.+=311.
Example 233
3-((R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-4,5-dihydro-1-indazol-1-
-yl)-N,N-dimethylbenzamide
[0640] (233a) To a solution of the enol (10.5 mg, 0.035 mmol) from
reaction 230d in HOAc (2 mL) was added 3-hydrazinobenzoic acid (6.4
mg, 1.2 eq). The mixture was stirred at room temperature for 5 h
and concentrated. The residue was dissolved in EtOAc (30 mL),
washed with 1 N HCl (5 mL), brine (5 mL), dried (MgSO.sub.4) and
concentrated. The crude material was used without purification.
[0641] (233b) HOBt monohydrate (14 mg, 3 eq), EDCI hydrochloride
(20 mg, 3 eq), Hunig base (0.059 mL, 10 eq) and a 2 M THF solution
of dimethylamine (0.085 mL, 5 eq) were added to the crude acid from
reaction 233a in acetonitrile (3 mL) at room temperature. After 15
h at room temperature, the mixture was concentrated and purified by
reverse phase HPLC (70-100% solvent B gradient) to give Example 233
(2.5 mg, 16% for 2 steps) as a yellow liquid. MS Found:
(M+H).sup.+=444.
Example 234
(5R)-1-(2,5-difluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-4,-
5-dihydro-1H-indazole
[0642] Using a procedure analogous to reaction Example 231, the
enol (15.6 mg, 0.052 mmol) from reaction 230d was reacted with
2,5-difluorophenylhydrazine to give Example 234 (2.5 mg, 12%). MS
found: (M+Na).sup.+=409.
Example 235
(5R)-1-(2,4-difluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-4,-
5-dihydro-1H-indazole
[0643] To a solution of the enol (20 mg, 0.067 mmol) from reaction
230d in HOAc (2 mL) were added 2,4-difluorophenylhydrazine
hydrochloride (14.5 mg, 1.2 eq) and sodium acetate (6.6 mg, 1.2
eq). The mixture was stirred at room temperature for 7 h,
concentrated and purified by silica gel chromatography
(EtOAc-hexanes, 0% to 15% gradient) to give Example 235 as a yellow
liquid (18.6 mg, 68%). MS found: (M+Na).sup.+=409.
Example 236
(R)-1-(3-chloro-4-fluorophenyl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethy-
l-4,5-dihydro-1H-indazole
[0644] Using a procedure analogous to Example 231, the enol (21 mg,
0.070 mmol) from reaction 230d was reacted with
3-chloro-4-fluorophenylhydrazine to give Example 236 (21.2 mg,
71%). MS found: (M+H).sup.+=425.
Example 237
(R)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-1-(pyridin-2-yl)-4,5-dihyd-
ro-1H-indazole
[0645] Using a procedure analogous to Example 235, the enol (22 mg,
0.073 mmol) from reaction 230d was reacted with 2-hydrazinopyridine
dihydrochloride to give Example 237 (15.4 mg, 43%). MS found:
(M+H).sup.+=374.
Example 238
(R)-1-(6-chloropyridazin-3-yl)-5-((R)-2-ethoxy-2-phenylethyl)-5,6-dimethyl-
-4,5-dihydro-1H-indazole
[0646] Using a procedure analogous to reaction Example 231, the
enol (18.4 mg, 0.060 mmol) from reaction 230d was reacted with
3-chloro-6-hydrazinopyridazine to give Example 238 (10.0 mg, 41%).
MS found: (M+Na).sup.+=431.
Example 239
(5R)-5-((R)-2-ethoxy-2-phenylethyl)-1-(2-fluorophenyl)-5,6-dimethyl-4,5-di-
hydro-1H-indazole
[0647] Using a procedure analogous to Example 235, the enol (22 mg,
0.073 mmol) from reaction 230d was reacted with
2-fluorophenylhydrazine hydrochloride to give Example 239 (3.8 mg,
13%). MS found: (M+H).sup.+=391.
Example 240
(R)-5-((R)-2-ethoxy-2-phenylethyl)-1-(3-fluorophenyl)-5,6-dimethyl-4,5-dih-
ydro-1H-indazole
[0648] Using a procedure analogous to Example 235, the enol (22 mg,
0.073 mmol) from reaction 230d was reacted with
3-fluorophenylhydrazine hydrochloride to give Example 240 (3.2 mg,
11%). MS found: (M+H).sup.+=391.
* * * * *